Comparison of Two Antibiotic Regimen (Meropenem Versus Meropenem+Moxifloxacin)in the Treatment of Severe Sepsis and Septic Shock (MaxSep)

Prospective, Randomized, Open, Multicentre Study About the Effect of an Empirical Antibiotic Monotherapy With Meropenem (Meronem®) Versus a Combination Therapy With Moxifloxacin (Avalox®) on Organ Dysfunction in Patients With Severe Sepsis and Septic Shock

Severe sepsis and septic shock are diseases of infectious origin with a high risk of death. Antibiotic therapy is mandatory but it is unknown whether one antibiotic alone is sufficient for initial therapy. The purpose of this study is to compare a therapy with meropenem alone or the combination of meropenem plus moxifloxacin in the treatment of severe sepsis/ septic shock. Patients randomly receive one of the two treatments for at least 7 days but not longer than 14 days.

Study Overview

• Status: Completed
• Conditions: Septic Shock; Severe Sepsis
• Intervention / Treatment: Drug: meropenem; Drug: meropenem, moxifloxacin

Detailed Description

Early intravenous empiric broad-spectrum antimicrobial therapy is an essential part of sepsis therapy. Inadequacy of empirical antibiotic therapy is associated with an increased mortality rate. Carbapenems are designed for empirical antimicrobial monotherapy. Combination therapy has been suggested but efficiency remains to be proven. In this study, antimicrobial monotherapy with meropenem is compared with a combination therapy of meropenem and moxifloxacin. It is hypothesized that the superior antibiotic therapy is associated with a lower overall organ dysfunction in sepsis. Study therapy lasts for at least 7 days unless microbiological results suggest otherwise. Study therapy may be extended to 14 days. Follow up examinations occur at 28 and 90 days. This investigator initiated study is supported by the German government (bmbf) and unrestricted industrial grants.

• Study Type: Interventional
• Enrollment (Actual): 600
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Aachen, Germany, 52074
    • University Hospital Aachen - Dep. of Anesthesiology
  • Augsburg, Germany, 86156
    • Klinikum Augsburg - Dep. of Anesthesiology and Intensive Care Medicine
  • Berlin, Germany, 10117
    • Charité Berlin - Dep. of Anesthesiology and Intensive Care Medicine
  • Berlin, Germany, 12313
    • Vivantes Klinikum Neukölln - Dep. of Anesthesiology, Intensive Care Medicine and Pain Therapy
  • Berlin, Germany, 13353
    • Charité Berlin - Campus Virchow-Klinikum - Dep. of Nephrology
  • Berlin, Germany, 10117
    • Charité Berlin - Dep. of Medicine (Cardiology, Angiology, Pneumology)
  • Berlin, Germany, 10117
    • Charité Campus Mitte -Dep.of Infectiology and Pneumonology
  • Berlin, Germany, 12203
    • Charité Campus Benjamin Franklin - Dep. of Medicine IV
  • Berlin, Germany, 12313
    • Vivantes Klinikum Neukölln - Cardiology
  • Bielefeld, Germany, 33617
    • Ev. Krankenhaus Gilead I - Dep. of Anesthesiology and Intensive Care Medicine
  • Bonn, Germany, 53105
    • University Hospital Bonn - Dep. of Anesthesiology and Intensive Care Medicine
  • Brandenburg, Germany, 14770
    • Städtisches Klinikum Brandenburg - Intensive Care Unit
  • Darmstadt, Germany, 64283
    • Klinikum Darmstadt - Dep. of Anesthesiology, Intensive Care Medicine and Pain Therapy
  • Dessau, Germany, 06847
    • Klinikum Dessau - Dep. of Medicine
  • Detmold, Germany, 32756
    • Hospital Lippe-Detmold - Dep. of Anesthesiology and Intensive Care Medicine
  • Dresden, Germany, 01067
    • Krankenhaus Dresden-Friedrichstadt
  • Dresden, Germany, 01307
    • University Hospital Dresden - Dep. of Anesthesiology and Intensive Care Med.
  • Erfurt, Germany, 99089
    • HELIOS Klinikum Erfurt - Dep. of Anesthesiology and Intensive Care Medicine
  • Erlangen, Germany, 91054
    • University Erlangen-Nürnberg - Dep. of Medicine IV
  • Freiburg, Germany, 79106
    • University Hospital Freiburg - Dep. of Medicine III
  • Greifswald, Germany, 17475
    • Ernst-Moritz-Arndt-Universität Greifswald - Dep. of Anesthesiology and Intensive Care Medicine
  • Greifswald, Germany, 17475
    • Ernst-Moritz-Arndt-Universität Greifswald, Dep. of Internal Medicine B
  • Göppingen, Germany, 73035
    • Klinik am Eichert - Dep. of Anesthesiology, Intensive Care Medicine, and Pain Therapy
  • Göttingen, Germany, 37075
    • Georg August Universität Göttingen - Dep. of Anesthesiology and Intensive Care Medicine
  • Halle, Germany, 06097
    • Martin-Luther-Universität Halle-Wittenberg - Dep. of Anesthesiology and Intensive Care Medicine
  • Halle, Germany, 06120
    • Hospital Martha-Maria Halle-Dölau gGmbH - Dep. of Anesthesiology and Intensive Care Medicine
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf - Dep. of Intensive Care Medicine
  • Hannover, Germany, 30167
    • Klinikum Hannover Nordstadt - Dep. of Anesthesiology and Intensive Care Medicine
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover, Dep. of Internal Medicine/ Pneumology
  • Heide, Germany, 25746
    • Westküstenklinikum Heide - Dep. of Anesthesiology and Intensive Care Medicine
  • Heidelberg, Germany, 69120
    • University Hospital Heidelberg - Dep. of Medicine IV
  • Heidelberg, Germany, 69120
    • University Hospital Heidelberg - Dep. of Visceral and Transplantation Surgery
  • Homburg/Saar, Germany, 66421
    • University Hospital Saarland - Deop. of Anesthesiology, Intensive Care Medicine, and Pain Therapy
  • Jena, Germany, 07747
    • University Hospital Jena, Dep. of Anesthesiology and Intensive Care Medicine
  • Kiel, Germany, 24105
    • University Hospital Kiel - Dep. of. Anesthesiology and Intensive Care Medicine
  • Köln, Germany, 50924
    • University Hospital Köln - Dep. of Internal Medicine I
  • Köln, Germany, 51109
    • Hospital Merheim - Dep. of Anesthesiology and Intensive Care Medicine
  • Leipzig, Germany, 04103
    • University Hospital Leipzig - Dep. of Anesthesiology and Intensive Care Medicine
  • Ludwigshafen, Germany, 67063
    • Hospital Ludwigshafen am Rhein - Dep. of Cardiac Surgery
  • Luedenscheid, Germany, 58515
    • Klinikum Lüdenscheid - Dep. of Anesthesiology
  • Mannheim, Germany, 68167
    • University Hospital Mannheim - Dep. of Medicine I
  • Munich, Germany, 80336
    • University Hospital Munich - Dep. of Internal Medicine
  • Munich, Germany, 81545
    • Hospital Munich Harlaching - Dep. of Internal Acute Medicine and Prevention
  • Munich, Germany, 81675
    • Klinikum rechts der Isar - Dep. of Anesthesiology
  • Münster, Germany, 48149
    • University Hospital Münster - Dep. of Anesthesiology and Intensive Care Medicine
  • Oldenburg, Germany, 26133
    • Klinikum Oldenburg - Dep. of Anesthesiology, Intensive Care Medicine, Emergency Medicine, Pain Therapy
  • Potsdam, Germany, 14467
    • Klinikum Ernst von Bergmann - Dep. of Anesthesiology and Intensive Care Medicine
  • Rostock, Germany, 18057
    • University Hospital Rostock - Dep. of Anesthesiology and Intensive Care Medicine
  • Siegen, Germany, 57074
    • Ev. Jung-Stilling-Krankenhaus - Dep. of Anesthesiology, Intensive Care Medicine, Emergency Medicine
  • Tübingen, Germany, 72076
    • University Hospital Tübingen - Dep. of Medicine
  • Ulm, Germany, 89081
    • University Hospital Ulm - Dep. of Internal Medicine II
  • Würzburg, Germany, 97070
    • Stiftung Juliusspital Würzburg - Dep. of Medicine (Cardiology)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Severe sepsis or septic shock according to ACCP/SCCM criteria
• Onset of severe sepsis or septic shock <24 h
• Informed consent
• Effective contraception in fertile women

Exclusion Criteria:

• Age <18 years
• Pregnancy
• Breast-feeding women
• Pretreatment with meropenem, imipenem, or ertapenem within the last 4 weeks (>1 daily dosage)
• Pretreatment with moxifloxacin,ciprofloxacin, or levofloxacin within the last 4 weeks (>1 daily dosage)
• Pretreatment with a pseudomonas effective cephalosporin (cefepime, ceftazidim, cefpirom) or piperacillin within the last 48 hours (>1 daily dosage).
• Pretreatment with other chinolones within the last 4 weeks (>1 daily dosage)
• Presence of infection where guidelines recommend another antimicrobial therapy than the study medication (i.e. endocarditis)
• Evidence or strong clinical suspicion of a microorganism where the study medication is known to be ineffective (i.e. tuberculosis, MRSA- or VRE-infection)
• Known allergy against meropenem or moxifloxacin
• Tendon disease or injury due to past quinolone therapy
• Congenital or acquired prolongation of QT-interval
• Concomitant medication which prolongs the QT-interval
• Electrolyte imbalance, especially uncorrected hypokalemia
• Clinically relevant bradycardia
• Clinically relevant cardiac dysfunction with reduced left-ventricular ejection fraction
• Symptomatic arrhythmias in the medical history
• Significant hepatic impairment (Child-Pugh C) or elevation of liver enzymes >5x the upper normal range
• No commitment to full patient support (i.e. DNR order)
• Patient's death is considered imminent due to coexisting disease
• Concomitant participation in another study or study participation with in the last 30 days.
• Relationship of the patient to study team member (i.e. colleague, relative)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: MeroMono; Monotherapy with meropenem	Drug: meropenem; Empirical antibiotic therapy with 3 x 1 g intravenous meropenem. Dosage is adjusted in case of renal dysfunction. Recommended duration of therapy is 7 days but can be extended up to 14 days.; Other Names: Meronem® (meropenem)
Active Comparator: MeroMoxi; Combination therapy with meropenem + moxifloxacin	Drug: meropenem, moxifloxacin; Empirical antibiotic therapy with 3 x 1 g intravenous meropenem plus 1 x 400 mg intravenous moxifloxacin. Dosage of meropenem is adjusted in case of renal dysfunction. Recommended duration of therapy is 7 days but can be extended up to 14 days.; Other Names: Meronem® (meropenem); Avalox® (moxifloxacin)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mean total SOFA score	study duration but not longer than 14 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Mortality	28 and 90 days
ICU and hospital length of stay
Response to therapy	day 7 and day 10
Clinical and microbiological cure	End of study therapy (day 7-14) and release from ICU (max. day 21)
Frequency of adverse events (AEs, SAEs, SUSARs)
Ventilator free days	28 and 90 days
Days without renal replacement therapy	28 and 90 days
Vasopressor free days	28 and 90 days
SOFA-subscores
Antibiotics free days	28 and 90 days
Costs of antibiotic therapy	ICU stay
Frequency of resistances to antibiotics	ICU stay
Frequency of new infections

Collaborators and Investigators

• Sponsor: Kompetenznetz Sepsis
• Collaborators: Bayer; AstraZeneca
• Investigators: Study Chair: Konrad Reinhart, MD, University Hospital Jena; Dep. of Anesthesiology and Intensive Care Medicine; Study Director: Markus Löffler, MD, University Leipzig; Koordinierungszentrum für Klinische Studien Leipzig (KKSL); Study Director: Thomas Deufel, MD, University Hopitel Jena, Institute for Medical Chemistry

Publications and helpful links

General Publications

• American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992 Jun;20(6):864-74.
• Reinhart K, Brunkhorst F, Bone H, Gerlach H, Grundling M, Kreymann G, Kujath P, Marggraf G, Mayer K, Meier-Hellmann A, Peckelsen C, Putensen C, Quintel M, Ragaller M, Rossaint R, Stuber F, Weiler N, Welte T, Werdan K; Deutsche Sepsis-Gesellschaft e.V. [Diagnosis and therapy of sepsis: guidelines of the German Sepsis Society Inc. and the German Interdisciplinary Society for Intensive and Emergency Medicine]. Anaesthesist. 2006 Jun;55 Suppl 1:43-56. German.
• Bochud PY, Bonten M, Marchetti O, Calandra T. Antimicrobial therapy for patients with severe sepsis and septic shock: an evidence-based review. Crit Care Med. 2004 Nov;32(11 Suppl):S495-512. doi: 10.1097/01.ccm.0000143118.41100.14.
• Harbarth S, Garbino J, Pugin J, Romand JA, Lew D, Pittet D. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med. 2003 Nov;115(7):529-35. doi: 10.1016/j.amjmed.2003.07.005.
• Safdar N, Handelsman J, Maki DG. Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta-analysis. Lancet Infect Dis. 2004 Aug;4(8):519-27. doi: 10.1016/S1473-3099(04)01108-9.
• Engel C, Brunkhorst FM, Bone HG, Brunkhorst R, Gerlach H, Grond S, Gruendling M, Huhle G, Jaschinski U, John S, Mayer K, Oppert M, Olthoff D, Quintel M, Ragaller M, Rossaint R, Stuber F, Weiler N, Welte T, Bogatsch H, Hartog C, Loeffler M, Reinhart K. Epidemiology of sepsis in Germany: results from a national prospective multicenter study. Intensive Care Med. 2007 Apr;33(4):606-18. doi: 10.1007/s00134-006-0517-7. Epub 2007 Feb 24.
• Pletz MW, Bloos F, Burkhardt O, Brunkhorst FM, Bode-Boger SM, Martens-Lobenhoffer J, Greer MW, Stass H, Welte T. Pharmacokinetics of moxifloxacin in patients with severe sepsis or septic shock. Intensive Care Med. 2010 Jun;36(6):979-83. doi: 10.1007/s00134-010-1864-y. Epub 2010 Mar 25.
• Brunkhorst FM, Oppert M, Marx G, Bloos F, Ludewig K, Putensen C, Nierhaus A, Jaschinski U, Meier-Hellmann A, Weyland A, Grundling M, Moerer O, Riessen R, Seibel A, Ragaller M, Buchler MW, John S, Bach F, Spies C, Reill L, Fritz H, Kiehntopf M, Kuhnt E, Bogatsch H, Engel C, Loeffler M, Kollef MH, Reinhart K, Welte T; 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. 2012 Jun 13;307(22):2390-9. doi: 10.1001/jama.2012.5833.

Helpful Links

• Competence Network Sepsis (SepNet)
• German Sepsis Society

Study record dates

Study Major Dates

• Study Start: October 1, 2007
• Primary Completion (Actual): April 1, 2010
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: September 21, 2007
• First Submitted That Met QC Criteria: September 21, 2007
• First Posted (Estimate): September 24, 2007

Study Record Updates

• Last Update Posted (Estimate): June 29, 2012
• Last Update Submitted That Met QC Criteria: June 28, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: sepsis; antibiotics; carbapenems; fluoroquinolones; Severe sepsis and septic shock
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Shock, Septic; Shock; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral, Combined; Contraceptives, Oral; Contraceptive Agents, Female; Moxifloxacin; Norgestimate, ethinyl estradiol drug combination; Meropenem
• Other Study ID Numbers: EudraCT 2006-006984-21; bmbf grant: 01 KI 01 06