Continuous Infusion Versus Intermittent Administration of Meropenem in Critically Ill Patients: A Multicenter Randomized Double Blind Trial
Overview
- Phase
- Phase 4
- Intervention
- Meropenem
- Conditions
- Antibiotic Resistant Infection
- Sponsor
- Università Vita-Salute San Raffaele
- Enrollment
- 607
- Locations
- 26
- Primary Endpoint
- Death or Emergence of new resistant bacteria
- Status
- Completed
- Last Updated
- 8 months ago
Overview
Brief Summary
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.
Investigators
Giovanni Landoni
MD, Full Professor
Università Vita-Salute San Raffaele
Eligibility Criteria
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
- •SIRS (Systemic Inflammatory Response Syndrome);
- •suspected or documented infection;
- •a SOFA score ≥
- •Septic shock defined as having all the following 1.Sepsis;
- •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)
Arms & Interventions
Continuous infusion
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 1. 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. 2. 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
Intervention: Meropenem
Bolus
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): 1. for Cl-Cr \> 50 ml/min 1 g every 6 hours on first 24 hours, every 8 hours after 2. for Cl-Cr \< 50 ml/min 1 g every 8 hours on first 24 hours, every 12 hours after
Intervention: Meropenem
Outcomes
Primary Outcomes
Death or Emergence of new resistant bacteria
Time Frame: day 28
composite outcome: 1. death from any cause at day 28 2. emergence of new XDR (extended drug resistant) or PDR (pan drug resistant) bacteria at day 28
Secondary Outcomes
- Death from any cause(day 90)
- Antibiotic-free days(up to day 28 or death)
- ICU - free days(day 28 or death)
- Cumulative SOFA-free point(up to day 28)