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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Severe Sepsis, Septic Shock

Intervention / Treatment
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* Drug: meropenem
* Drug: meropenem, moxifloxacin


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: MeroMono<br>Monotherapy with meropenem | Drug: meropenem<br>* 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.<br>* Other names: Meronem® (meropenem);|
| Active Comparator: MeroMoxi<br>Combination therapy with meropenem + moxifloxacin | Drug: meropenem, moxifloxacin<br>* 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.<br>* Other names: Avalox® (moxifloxacin);|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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 |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis, antibiotics, carbapenems, fluoroquinolones, Severe sepsis and septic shock