Clinical Outcome Study of High-dose Meropenem in Sepsis and Septic Shock Patients

Study Overview
=================
Brief Summary
-----------------
Sepsis and septic shock patients are considered to have a high risk of complications and death. Appropriate antimicrobial therapy plays an important role in determining outcomes in septic patients. However, pathophysiologic changes associated with critical illness have an impact on pharmacokinetics of antimicrobials. In addition, increasing bacterial resistance is also a growing concern, especially in intensive care units., Consequently, standard antimicrobial dose may not be sufficient to achieve pharmacokinetic/pharmacodynamic target in sepsis and septic shock patients. The purpose of this study is to compare a therapy between meropenem standard dose and meropenem high dose in the treatment of sepsis and septic shock

Official Title
-----------------
Clinical Outcome Study of High-dose Meropenem in Sepsis and Septic Shock Patients

Conditions
-----------------
Sepsis, Septic Shock, Critical Illness, Carbapenem, Pharmacokinetic, Pharmacodynamic, Clinical Outcome, Organ Failure, Multiple, Morality

Intervention / Treatment
-----------------
* Drug: Meropenem standard dose
* Drug: Meropenem high dose


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults (18 years and older) with sepsis and/or septic shock according to SEPSIS-3 criteria and receive meropenem within 1 hour after diagnosis Informed consent signed by patient or their legally authorized representative Exclusion Criteria: Subjects with infective endocarditis Subjects with central nervous system infection Subjects who requires surgical condition within 72 hours after randomization Subjects on extracorporeal membrane oxygenation (ECMO) within 3 days after randomization Subjects with active seizure History of receiving meropenem within 1 week prior to randomization Pregnancy women and lactation Known allergy to meropenem Not complete a 72-hour course of empirical meropenem treatment

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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: Meropenem standard dose<br>Meropenem 1 g every 8 hours | Drug: Meropenem standard dose<br>* Empirical with 1 g meropenem intravenous infusion in 30 minutes then 1 g intravenous infusion in 3 hours every 8 hours. Dosage is adjusted in case of renal dysfunction. Duration of therapy is varied regarding source(s) of infection.<br>|
| Active Comparator: Meropenem high dose<br>Meropenem 2 g every 8 hours | Drug: Meropenem high dose<br>* Empirical with 2 g meropenem intravenous infusion in 30 minutes then 2 g intravenous infusion in 3 hours every 8 hours. Dosage is adjusted in case of renal dysfunction. Duration of therapy is varied regarding source(s) of infection<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SOFA score change | The Sequential organ failure assessment (SOFA) score describe the time course of multiple organ dysfunction. The SOFA score is composed of scores for six organ systems (respiratory, cardiovascular, neurological, hepatic, renal and coagulation). The function of six organ systems is scored from 0 (no organ dysfunction) to 4 (severe organ dysfunction), and the individual organ scores are then summed to a total score between 0 and 24. Primary outcome is assessing change between SOFA score at baseline and SOFA score at day 4 after treatment by meropenem | Change from Baseline SOFA score at day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | In hospital mortality | 14 and 28 days | 
| Clinical cure | Composite of: Persistent fever and/or Stable or increased white blood cell count | Day 3, 5, 7, 10 and 14 | 
| Microbiological cure | Elimination of the study entry pathogen within 14 days after received meropenem Bacteremia: no growth in blood cultures Intra-abdominal infection: no growth in blood cultures UTI: uropathogen growth of less than 10^4 CFU/mL in women or less than 10^3 CFU/mL in men HAP/VAP: pathogen in sputum culture growth of less than 10^3 CFU/mL SSTI: no growth in blood cultures | Day 3, 5, 7, 10 and 14 | 
| Duration of vasopressor agents | Time interval (day) from time of vasopressor agents initiation to time to vasopressor agents discontinuation | 14 and 28 days | 
| Duration of mechanical ventilator | Time interval (day) of mechanical ventilator | 14 and 28 days | 
| Length of ICU stay | Time interval (day) from ICU admission (after randomization) to ICU discharge | 14 and 28 days | 
| Length of hospital stay | Time interval (day) from hospital admission (after randomization) to hospital discharge | 14 and 28 days | 
| %T > MIC | % time of meropenem concentration above MIC | Day 1 |