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

Septic Shock Clinical Trial

— MaxSep  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00534287
• Other study ID #: EudraCT 2006-006984-21
• Secondary ID: bmbf grant: 01 K
• Status: Completed
• Phase: Phase 3
• First received: September 21, 2007
• Last updated: June 28, 2012
• Start date: October 2007
• Est. completion date: June 2010

Study information

• Verified date: June 2012
• Source: Kompetenznetz Sepsis
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 600
• Est. completion date: June 2010
• Est. primary completion date: April 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Sepsis
• Septic Shock
• Severe Sepsis
• Shock
• Shock, Septic
• Toxemia

Intervention

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.
• 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.

Locations

Country	Name	City	State
Germany	University Hospital Aachen - Dep. of Anesthesiology	Aachen
Germany	Klinikum Augsburg - Dep. of Anesthesiology and Intensive Care Medicine	Augsburg
Germany	Charité Berlin - Campus Virchow-Klinikum - Dep. of Nephrology	Berlin
Germany	Charité Berlin - Dep. of Anesthesiology and Intensive Care Medicine	Berlin
Germany	Charité Berlin - Dep. of Medicine (Cardiology, Angiology, Pneumology)	Berlin
Germany	Charité Campus Benjamin Franklin - Dep. of Medicine IV	Berlin
Germany	Charité Campus Mitte -Dep.of Infectiology and Pneumonology	Berlin
Germany	Vivantes Klinikum Neukölln - Cardiology	Berlin
Germany	Vivantes Klinikum Neukölln - Dep. of Anesthesiology, Intensive Care Medicine and Pain Therapy	Berlin
Germany	Ev. Krankenhaus Gilead I - Dep. of Anesthesiology and Intensive Care Medicine	Bielefeld
Germany	University Hospital Bonn - Dep. of Anesthesiology and Intensive Care Medicine	Bonn
Germany	Städtisches Klinikum Brandenburg - Intensive Care Unit	Brandenburg
Germany	Klinikum Darmstadt - Dep. of Anesthesiology, Intensive Care Medicine and Pain Therapy	Darmstadt
Germany	Klinikum Dessau - Dep. of Medicine	Dessau
Germany	Hospital Lippe-Detmold - Dep. of Anesthesiology and Intensive Care Medicine	Detmold
Germany	Krankenhaus Dresden-Friedrichstadt	Dresden
Germany	University Hospital Dresden - Dep. of Anesthesiology and Intensive Care Med.	Dresden
Germany	HELIOS Klinikum Erfurt - Dep. of Anesthesiology and Intensive Care Medicine	Erfurt
Germany	University Erlangen-Nürnberg - Dep. of Medicine IV	Erlangen
Germany	University Hospital Freiburg - Dep. of Medicine III	Freiburg
Germany	Klinik am Eichert - Dep. of Anesthesiology, Intensive Care Medicine, and Pain Therapy	Göppingen
Germany	Georg August Universität Göttingen - Dep. of Anesthesiology and Intensive Care Medicine	Göttingen
Germany	Ernst-Moritz-Arndt-Universität Greifswald - Dep. of Anesthesiology and Intensive Care Medicine	Greifswald
Germany	Ernst-Moritz-Arndt-Universität Greifswald, Dep. of Internal Medicine B	Greifswald
Germany	Hospital Martha-Maria Halle-Dölau gGmbH - Dep. of Anesthesiology and Intensive Care Medicine	Halle
Germany	Martin-Luther-Universität Halle-Wittenberg - Dep. of Anesthesiology and Intensive Care Medicine	Halle
Germany	Universitätsklinikum Hamburg-Eppendorf - Dep. of Intensive Care Medicine	Hamburg
Germany	Klinikum Hannover Nordstadt - Dep. of Anesthesiology and Intensive Care Medicine	Hannover
Germany	Medizinische Hochschule Hannover, Dep. of Internal Medicine/ Pneumology	Hannover
Germany	Westküstenklinikum Heide - Dep. of Anesthesiology and Intensive Care Medicine	Heide
Germany	University Hospital Heidelberg - Dep. of Medicine IV	Heidelberg
Germany	University Hospital Heidelberg - Dep. of Visceral and Transplantation Surgery	Heidelberg
Germany	University Hospital Saarland - Deop. of Anesthesiology, Intensive Care Medicine, and Pain Therapy	Homburg/Saar
Germany	University Hospital Jena, Dep. of Anesthesiology and Intensive Care Medicine	Jena
Germany	University Hospital Kiel - Dep. of. Anesthesiology and Intensive Care Medicine	Kiel
Germany	Hospital Merheim - Dep. of Anesthesiology and Intensive Care Medicine	Köln
Germany	University Hospital Köln - Dep. of Internal Medicine I	Köln
Germany	University Hospital Leipzig - Dep. of Anesthesiology and Intensive Care Medicine	Leipzig
Germany	Hospital Ludwigshafen am Rhein - Dep. of Cardiac Surgery	Ludwigshafen
Germany	Klinikum Lüdenscheid - Dep. of Anesthesiology	Luedenscheid
Germany	University Hospital Mannheim - Dep. of Medicine I	Mannheim
Germany	Hospital Munich Harlaching - Dep. of Internal Acute Medicine and Prevention	Munich
Germany	Klinikum rechts der Isar - Dep. of Anesthesiology	Munich
Germany	University Hospital Munich - Dep. of Internal Medicine	Munich
Germany	University Hospital Münster - Dep. of Anesthesiology and Intensive Care Medicine	Münster
Germany	Klinikum Oldenburg - Dep. of Anesthesiology, Intensive Care Medicine, Emergency Medicine, Pain Therapy	Oldenburg
Germany	Klinikum Ernst von Bergmann - Dep. of Anesthesiology and Intensive Care Medicine	Potsdam
Germany	University Hospital Rostock - Dep. of Anesthesiology and Intensive Care Medicine	Rostock
Germany	Ev. Jung-Stilling-Krankenhaus - Dep. of Anesthesiology, Intensive Care Medicine, Emergency Medicine	Siegen
Germany	University Hospital Tübingen - Dep. of Medicine	Tübingen
Germany	University Hospital Ulm - Dep. of Internal Medicine II	Ulm
Germany	Stiftung Juliusspital Würzburg - Dep. of Medicine (Cardiology)	Würzburg

Sponsors (3)

Lead Sponsor	Collaborator
Kompetenznetz Sepsis	AstraZeneca, Bayer

Country where clinical trial is conducted

Germany, 

References & Publications (8)

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. Review. — View 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. Review. — View Citation

Brunkhorst FM, Oppert M, Marx G, Bloos F, Ludewig K, Putensen C, Nierhaus A, Jaschinski U, Meier-Hellmann A, Weyland A, Gründling M, Moerer O, Riessen R, Seibel A, Ragaller M, Büchler MW, John S, Bach F, Spies C, Reill L, Fritz H, Kiehntopf M, Kuhnt E, Bo — View 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. Epub 2007 Feb 24. — View 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. — View Citation

Pletz MW, Bloos F, Burkhardt O, Brunkhorst FM, Bode-Böger 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. — View Citation

Reinhart K, Brunkhorst F, Bone H, Gerlach H, Gründling M, Kreymann G, Kujath P, Marggraf G, Mayer K, Meier-Hellmann A, Peckelsen C, Putensen C, Quintel M, Ragaller M, Rossaint R, Stüber 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. Review. German. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean total SOFA score		study duration but not longer than 14 days	No
Secondary	Mortality		28 and 90 days	No
Secondary	ICU and hospital length of stay			No
Secondary	Response to therapy		day 7 and day 10	No
Secondary	Clinical and microbiological cure		End of study therapy (day 7-14) and release from ICU (max. day 21)	No
Secondary	Frequency of adverse events (AEs, SAEs, SUSARs)			Yes
Secondary	Ventilator free days		28 and 90 days	No
Secondary	Days without renal replacement therapy		28 and 90 days	No
Secondary	Vasopressor free days		28 and 90 days	No
Secondary	SOFA-subscores			No
Secondary	Antibiotics free days		28 and 90 days	Yes
Secondary	Costs of antibiotic therapy		ICU stay	No
Secondary	Frequency of resistances to antibiotics		ICU stay	Yes
Secondary	Frequency of new infections			Yes

External Links

•   Competence Network Sepsis (SepNet)
•   Competence Networks in Medicine
•   German Sepsis Society