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

• Mortality [ Time Frame: 28 and 90 days ] [ Designated as safety issue: No ]
• ICU and hospital length of stay [ Designated as safety issue: No ]
• Response to therapy [ Time Frame: day 7 and day 10 ] [ Designated as safety issue: No ]
• Clinical and microbiological cure [ Time Frame: End of study therapy (day 7-14) and release from ICU (max. day 21) ] [ Designated as safety issue: No ]
• Frequency of adverse events (AEs, SAEs, SUSARs) [ Designated as safety issue: Yes ]
• Ventilator free days [ Time Frame: 28 and 90 days ] [ Designated as safety issue: No ]
• Days without renal replacement therapy [ Time Frame: 28 and 90 days ] [ Designated as safety issue: No ]
• Vasopressor free days [ Time Frame: 28 and 90 days ] [ Designated as safety issue: No ]
• SOFA-subscores [ Designated as safety issue: No ]
• Antibiotics free days [ Time Frame: 28 and 90 days ] [ Designated as safety issue: Yes ]
• Costs of antibiotic therapy [ Time Frame: ICU stay ] [ Designated as safety issue: No ]
• Frequency of resistances to antibiotics [ Time Frame: ICU stay ] [ Designated as safety issue: Yes ]
• Frequency of new infections [ Designated as safety issue: Yes ]

• Mortality [ Time Frame: 80 and 90 days ]
• ICU and hospital length of stay
• Response to therapy [ Time Frame: day 7 and day 10 ]
• Clinical and microbiological cure [ Time Frame: End of study therapy (day 7-14) and release from ICU (max. day 21) ]
• Frequency of adverse events (AEs, SAEs, SUSARs)
• Ventilator free days [ Time Frame: 28 and 90 days ]
• Days without renal replacement therapy [ Time Frame: 28 and 90 days ]
• Vasopressor free days [ Time Frame: 28 and 90 days ]
• SOFA-subscores
• Antibiotics free days [ Time Frame: 28 and 90 days ]
• Costs of antibiotic therapy
• Frequency of resistances to antibiotics
• Frequency of new infections

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.

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.

• Severe Sepsis
• Septic Shock

• 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 Name: Meronem® (meropenem)
• 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)

• Active Comparator: MeroMono
  Monotherapy with meropenem
  Intervention: Drug: meropenem
• Active Comparator: MeroMoxi
  Combination therapy with meropenem + moxifloxacin
  Intervention: Drug: meropenem, moxifloxacin

• 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, 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.
• [No authors listed] 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.
• 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. Review. 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. Review.
• 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.
• 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.
• 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.
• 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. Epub 2010 Mar 25.

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)

• AstraZeneca
• Bayer