Bolus Versus Continuous Infusion of Meropenem

Study Overview
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Brief Summary
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This study arises from the need to optimize antibacterial drug usage to face increasing drug resistance among gram-negative pathogens in intensive care units. Gram-negative organisms are responsible for 70% of drug-resistant infections acquired in the intensive care unit. Meropenem is a β-lactam, carbapenem, antibacterial agent usually administered by intermittent infusion. As β-lactam efficacy is determined by the time in which the drug concentration exceeds the minimum inhibiting concentration of the target pathogen, intermittent infusion of this short half-lived drug can lead to precipitous drops in serum drug levels, an occurrence linked to emergence of resistant pathogens. The investigators hypothesize a beneficial effect of a continuous meropenem infusion on mortality and emergence of drug resistant pathogens. All patients enrolled will receive 1 g of meropenem bolus. After that, subjects will be randomized to receive a continuous infusion of study drug 3g/day or a bolus administration of the same amount of drugs. The investigators expect a reduction of mortality and emergence of extensive or pan drug resistant pathogens from 52 to 40% in the continuous infusion group.

Official Title
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Continuous Infusion Versus Intermittent Administration of Meropenem in Critically Ill Patients: A Multicenter Randomized Double Blind Trial

Conditions
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Antibiotic Resistant Infection, Critical Illness

Intervention / Treatment
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* Drug: Meropenem


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Will be enrolled patients who: Are able to express informed consent or the latter can be given by his/her next of kin or as requested by Ethical Committee. Need a new antibiotic treatment, by clinical judgment, with meropenem Are admitted to ICU Have Sepsis or septic shock. Sepsis defined as having all the following 1. SIRS (Systemic Inflammatory Response Syndrome); 2. suspected or documented infection; 3. a SOFA score ≥ 2. Septic shock defined as having all the following 1.Sepsis; 2. Persisting hypotension requiring vasopressors to maintain MAP ≥65mmHg and having a serum lactate level >2 mmol/L (18mg/dL) despite adequate volume resuscitation. Exclusion Criteria: Will be excluded patients who: Are able to express informed consent and deny it Are already receiving study drug or other carbapenem both as a bolus or continuous infusion Have a known allergy or intolerance to study drug, to other carbapenem antibacterial agents or severe allergic reaction to β-lactam antibacterial agents or to anhydrous sodium carbonate (study drug excipient) Have a little chance of survival, as defined by a SAPS II score greater than 65 Have concomitant acquired immunodeficiency syndrome (stage 3 according to CDC) Received immunosuppressant or long-term corticosteroid therapy (more than 0.5 mg/kg/day for over 30 days)

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Continuous infusion<br>Patient randomized to continuous infusion group, will receive a continuous infusion of meropenem according to their renal function (creatinine clearance -ClCr- estimated by Cockcroft-Gault formula and study day for ClCr > 50 ml/min: 3 g / day, prepared as follows: 10 mg/ml of meropenem in NaCl 0.9% at 12,5 ml/h. for ClCr < 50 ml/min: 2 g / day, prepared as follows: 10 mg/ml of meropenem in NaCl 0.9% at 8,3 ml/h. This solution will be replaced every time its duration exceeds the stability in use stated by the producer | Drug: Meropenem<br>* Meropenem or injection vials to be re-constituted in a solution of NaCl 0.9%.<br>|
| Active Comparator: Bolus<br>Patient randomized to bolus group, will receive a bolus infusion of meropenem according to their renal function (creatinine clearance -ClCr- estimated by Cockcroft-Gault formula): for Cl-Cr > 50 ml/min 1 g every 6 hours on first 24 hours, every 8 hours after for Cl-Cr < 50 ml/min 1 g every 8 hours on first 24 hours, every 12 hours after | Drug: Meropenem<br>* Meropenem or injection vials to be re-constituted in a solution of NaCl 0.9%.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death or Emergence of new resistant bacteria | composite outcome: death from any cause at day 28 emergence of new XDR (extended drug resistant) or PDR (pan drug resistant) bacteria at day 28 | day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death from any cause | Death from any cause | day 90 | 
| Antibiotic-free days | Proportion of days from randomization to day 28 or death in which subject didn't receive any antibiotics (excluding anti-fungal anti-viral drugs) | up to day 28 or death | 
| ICU - free days | Number of days from randomization to day 28 (or death) in which the subject is outside the ICU. For any discharge lasting less than 48h, no ICU-free day will be computed. Re-admission lasting less than 24 hours will not reduce ICU-free days. Patients that will not survive outside ICU for at least 48 hours, will have a ICU-free day of zero | day 28 or death | 
| Cumulative SOFA-free point | SOFA score will be evaluated every day up to day 28. SOFA-free daily score is 24 (maximum SOFA) minus actual SOFA. Cumulative SOFA-free is the sum of SOFA-free daily from randomization to date 28. Patients dead before day 28 can't ameliorate their SOFA-free score. This way, the higher the cumulative SOFA-free, the higher is the amelioration of the patient and his probability of survival. | up to day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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meropenem, antibiotic resistance, critical illness, β-lactams, continuous antibacterial drug infusion, mortality