Clinical trial NCT00534287: Comparison of Two Antibiotic Regimen (Meropenem Versus Meropenem+Moxifloxacin)in the Treatment of Severe Sepsis and Septic Shock
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Severe Sepsis
Septic Shock
Keywords: sepsis
antibiotics
carbapenems
fluoroquinolones
Severe sepsis and septic shock
Lead sponsor: Kompetenznetz Sepsis
Sponsor class: NETWORK
Collaborators: name: AstraZeneca
name: Bayer
First posted: 2007-09-24
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Mean total SOFA score
timeFrame: study duration but not longer than 14 days
Secondary outcomes:
measure: Mortality
timeFrame: 28 and 90 days
measure: ICU and hospital length of stay
measure: Response to therapy
timeFrame: day 7 and day 10
measure: Clinical and microbiological cure
timeFrame: End of study therapy (day 7-14) and release from ICU (max. day 21)
measure: Frequency of adverse events (AEs, SAEs, SUSARs)
measure: Ventilator free days
timeFrame: 28 and 90 days
measure: Days without renal replacement therapy
timeFrame: 28 and 90 days
measure: Vasopressor free days
timeFrame: 28 and 90 days
measure: SOFA-subscores
measure: Antibiotics free days
timeFrame: 28 and 90 days
measure: Costs of antibiotic therapy
timeFrame: ICU stay
measure: Frequency of resistances to antibiotics
timeFrame: ICU stay
measure: Frequency of new infections
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: University Hospital Aachen - Dep. of Anesthesiology
city: Augsburg
country: Germany
facility: Klinikum Augsburg - Dep. of Anesthesiology and Intensive Care Medicine
city: Berlin
country: Germany
facility: Charité Berlin - Dep. of Anesthesiology and Intensive Care Medicine
city: Berlin
country: Germany
facility: Charité Berlin - Dep. of Medicine (Cardiology, Angiology, Pneumology)
city: Berlin
country: Germany
facility: Charité Campus Mitte -Dep.of Infectiology and Pneumonology
city: Berlin
country: Germany
facility: Charité Campus Benjamin Franklin - Dep. of Medicine IV
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln - Cardiology
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln - Dep. of Anesthesiology, Intensive Care Medicine and Pain Therapy
city: Berlin
country: Germany
facility: Charité Berlin - Campus Virchow-Klinikum - Dep. of Nephrology
city: Bielefeld
country: Germany
facility: Ev. Krankenhaus Gilead I - Dep. of Anesthesiology and Intensive Care Medicine
city: Bonn
country: Germany
facility: University Hospital Bonn - Dep. of Anesthesiology and Intensive Care Medicine
city: Brandenburg
country: Germany
facility: Städtisches Klinikum Brandenburg - Intensive Care Unit
city: Darmstadt
country: Germany
facility: Klinikum Darmstadt - Dep. of Anesthesiology, Intensive Care Medicine and Pain Therapy
city: Dessau
country: Germany
facility: Klinikum Dessau - Dep. of Medicine
city: Detmold
country: Germany
facility: Hospital Lippe-Detmold - Dep. of Anesthesiology and Intensive Care Medicine
city: Dresden
country: Germany
facility: Krankenhaus Dresden-Friedrichstadt
city: Dresden
country: Germany
facility: University Hospital Dresden - Dep. of Anesthesiology and Intensive Care Med.
city: Erfurt
country: Germany
facility: HELIOS Klinikum Erfurt - Dep. of Anesthesiology and Intensive Care Medicine
city: Erlangen
country: Germany
facility: University Erlangen-Nürnberg - Dep. of Medicine IV
city: Freiburg
country: Germany
facility: University Hospital Freiburg - Dep. of Medicine III
city: Greifswald
country: Germany
facility: Ernst-Moritz-Arndt-Universität Greifswald - Dep. of Anesthesiology and Intensive Care Medicine
city: Greifswald
country: Germany
facility: Ernst-Moritz-Arndt-Universität Greifswald, Dep. of Internal Medicine B
city: Göppingen
country: Germany
facility: Klinik am Eichert - Dep. of Anesthesiology, Intensive Care Medicine, and Pain Therapy
city: Göttingen
country: Germany
facility: Georg August Universität Göttingen - Dep. of Anesthesiology and Intensive Care Medicine
city: Halle
country: Germany
facility: Martin-Luther-Universität Halle-Wittenberg - Dep. of Anesthesiology and Intensive Care Medicine
city: Halle
country: Germany
facility: Hospital Martha-Maria Halle-Dölau gGmbH - Dep. of Anesthesiology and Intensive Care Medicine
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf - Dep. of Intensive Care Medicine
city: Hannover
country: Germany
facility: Klinikum Hannover Nordstadt - Dep. of Anesthesiology and Intensive Care Medicine
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Dep. of Internal Medicine/ Pneumology
city: Heidelberg
country: Germany
facility: University Hospital Heidelberg - Dep. of Medicine IV
city: Heidelberg
country: Germany
facility: University Hospital Heidelberg - Dep. of Visceral and Transplantation Surgery
city: Heide
country: Germany
facility: Westküstenklinikum Heide - Dep. of Anesthesiology and Intensive Care Medicine
city: Homburg/Saar
country: Germany
facility: University Hospital Saarland - Deop. of Anesthesiology, Intensive Care Medicine, and Pain Therapy
city: Jena
country: Germany
facility: University Hospital Jena, Dep. of Anesthesiology and Intensive Care Medicine
city: Kiel
country: Germany
facility: University Hospital Kiel - Dep. of. Anesthesiology and Intensive Care Medicine
city: Köln
country: Germany
facility: University Hospital Köln - Dep. of Internal Medicine I
city: Köln
country: Germany
facility: Hospital Merheim - Dep. of Anesthesiology and Intensive Care Medicine
city: Leipzig
country: Germany
facility: University Hospital Leipzig - Dep. of Anesthesiology and Intensive Care Medicine
city: Ludwigshafen
country: Germany
facility: Hospital Ludwigshafen am Rhein - Dep. of Cardiac Surgery
city: Luedenscheid
country: Germany
facility: Klinikum Lüdenscheid - Dep. of Anesthesiology
city: Mannheim
country: Germany
facility: University Hospital Mannheim - Dep. of Medicine I
city: Munich
country: Germany
facility: University Hospital Munich - Dep. of Internal Medicine
city: Munich
country: Germany
facility: Hospital Munich Harlaching - Dep. of Internal Acute Medicine and Prevention
city: Munich
country: Germany
facility: Klinikum rechts der Isar - Dep. of Anesthesiology
city: Münster
country: Germany
facility: University Hospital Münster - Dep. of Anesthesiology and Intensive Care Medicine
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg - Dep. of Anesthesiology, Intensive Care Medicine, Emergency Medicine, Pain Therapy
city: Potsdam
country: Germany
facility: Klinikum Ernst von Bergmann - Dep. of Anesthesiology and Intensive Care Medicine
city: Rostock
country: Germany
facility: University Hospital Rostock - Dep. of Anesthesiology and Intensive Care Medicine
city: Siegen
country: Germany
facility: Ev. Jung-Stilling-Krankenhaus - Dep. of Anesthesiology, Intensive Care Medicine, Emergency Medicine
city: Tübingen
country: Germany
facility: University Hospital Tübingen - Dep. of Medicine
city: Ulm
country: Germany
facility: University Hospital Ulm - Dep. of Internal Medicine II
city: Würzburg
country: Germany
facility: Stiftung Juliusspital Würzburg - Dep. of Medicine (Cardiology)
Study officials:
affiliation: University Hospital Jena; Dep. of Anesthesiology and Intensive Care Medicine
name: Konrad Reinhart, MD
role: STUDY_CHAIR
affiliation: University Leipzig; Koordinierungszentrum für Klinische Studien Leipzig (KKSL)
name: Markus Löffler, MD
role: STUDY_DIRECTOR
affiliation: University Hopitel Jena, Institute for Medical Chemistry
name: Thomas Deufel, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.