Beta-lactam Intermittent vs Continuous infusion and Combination antibiotic therapy in Sepsis
Conditions
Interventions
Product Name: Ceftazidime
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: Ceftazidime
CAS Number: 72558-82-8
Concentration unit: g gram(s)
Concentration type
Sponsors
APHP
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients admitted to ICU meeting all the following criteria will be eligible for inclusion: • Adults (= 18 years) • Hospital-acquired sepsis diagnosed in the past 24 hours (according to sepsis 3.0 definitions) • One of the following risk factors for multidrug resistant pathogens: - Prior intravenous antibiotic use within 7 days prior to sepsis onset with the exception of antibiotic effective only against Gram-positive bacteria, penicillin A and macrolides - Prolonged hospital stay (= 15 days of hospitalization) within 90 days prior to the occurrence of sepsis - Prolonged mechanical ventilation (= 5 days on mechanical ventilation) within 90 days prior to sepsis onset - Patients with indwelling devices (dialysis access lines, intravascular lines, urinary catheter, endotracheal or tracheostomy tube, gastrostomy or jejunostomy feeding tube) - Patients known to be infected, colonized or carriers of MDR gram negative bacteria in the past 3 months • Appropriate bacteriological sampling performed before starting antimicrobial therapy • Expected stay in ICU of more than 3 days Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 600 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Patients meeting one of the following criteria will not be considered for inclusion: o Knowledge of the germ of inclusion infection resistant to all the proposed beta-lactams or resistant to amikacin o Need for extrarenal treatment at inclusion according to the criteria of Gaudry et al. o Severe known hypersensitivity (eg, anaphylactic reaction, severe skin reaction) to any beta-lactam antibiotic (eg, penicillins or cephalosporins or carbapenems) or to any of its excipients. o Known contraindication to the aminoglycoside family including o Hypersensitivity o Cirrhosis of grades B and C according to the Child-Pugh classification. o Myasthenia gravis. o Simultaneous administration of another aminoglycoside o Association with ataluren o Non-complicated urinary tract infection (with the exception of acute prostatitis) o Bone marrow transplant or chemotherapy-induced neutropenia o Infections for which long-term antibiotic treatment > 8 days is strongly recommended (i.e., infective endocarditis, osteoarticular infections, anterior mediastinitis after cardiac surgery, hepatic or cerebral abscesses, chronic prostatitis for instance o Presence of antibiotic therapy for the new sepsis (if sepsis acquired in the hospital outside the resuscitation> 2 doses of antibiotics) o Hospitalization in a short stay hospital of more than 48 hours o Limitation of life support (comfort care applied only) at the time of screening o Enrolment to another interventional study o Pregnancy or breastfeeding o Subject deprived of freedom, subject under a legal protective measure o Non affiliation to any health insurance system o Refusal to participate to the study (patient or legal representative or family member or close relative if present)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To compare the 30-day mortality of patients with hospital-acquired sepsis in the ICU according to the mode of administration of the pivotal ßL antibiotic (CID group vs. IID group). Co-primary objective: To compare the MAKE 30 (Major Adverse Kidney Events within 30 days) between patients that will receive an appropriate monotherapy with ßL (AMT group) or an appropriate combination therapy with ßL and 5 days of AG (ACT group). ;Secondary Objective: Secondary objectives include the following comparisons, according to both interventions 1)30-day mortality in patients with proven Gram-negative infection (GNI), with proven non-fermentative GNI, with proven GNI for which the minimum inhibitory concentration (MIC) of the ßL used were higher to the breakpoints according to the European committee on Antimicrobial Susceptibility Testing (EUCAST). 2)30-day mortality in patients that received non-carbapenem-ßL 3)30-day clinical recovery 4)PK-PD target attainment at day 1 and day 3 5)Superinfection (primary infection site) or new infection (different infection site) at day 30 due to a GNB resistant to the ßL administered at inclusion 6)Microbiological failure persistence of the same microorganism at the same site at end-of-therapy (EOT) or within 7 days after EOT. For the point 7 to 12 please confere the protocole because there are a lot of words ;Primary end point(s): Primary endpoint The primary endpoint is the mortality rate at day 30 between CID and IID groups. Co-primary endpoint The co-primary criterion is the percentage of patients with a MAKE 30, i.e. when patients met one of the following criteria within day 30: in-hospital mortality, receipt of renal replacement therapy (RRT) or persistent renal dysfunction (discharge serum creatinine/baseline serum creatinine =200%) between AMT and ACT groups. ;Timepoint(s) of evaluation of this end point: -inclusion period: 24 months -participation period (treatment + follow-up): 7 days of treatment and follo | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary objectives Secondary objectives include the following comparisons, according to both interventions 1) 30-day mortality in patients (i) with proven Gram-negative infection (GNI), (ii) with proven non-fermentative GNI, (iii) with proven GNI for which the minimum inhibitory concentration (MIC) of the ßL used were higher to the breakpoints according to the European committee on Antimicrobial Susceptibility Testing (EUCAST). 2) 30-day mortality in patients that received non-carbapenem-ßL 3) 30-day clinical recovery 4) PK-PD target attainment at day 1 and day 3 5) Superinfection (primary infection site) or new infection (different infection site) at day 30 due to a GNB resistant to the ßL administered at inclusion 6) Microbiological failure persistence of the same microorganism at the same site at end-of-therapy (EOT) or within 7 days after EOT. 7) New carriage, colonization or infection with one of the following BMR-GNB: at days 3, 7 and 30: - extended spectrum beta-lactamases (ESBL) Enterobacteriaceae - ticarcillin-resistant Pseudomonas aeruginosa, Acinetobacter baumannii Stenotrophomonas maltophilia - extended-spectrum ß-lactam-producing Entero bacteriaceae - high-concentration cephalosporinase producing AmpC Enterobacteriaceae; 8) New carriage, colonization or infection with Pseudomonas aeruginosa not susceptible to the ßL administered at days 3, 7 and 30 9) Duration of organ failure between day 1 and day 30 10) Occurrence of adverse events at day 30 11) Length of ICU and hospital stays 12) 180-day mortality Secondary endpoints The clinical secondary endpoints are as follows: 1. Mortality rate at day 30 in patients with (i) proven GNI, (ii) proven non-fermentative GNI, (iii) proven GNI for which the MIC of the ßL used were higher to the accepted break-points 2. Mortality rate at day 30 in patients that received non-carbapenem-ßL 3. Clinical recovery at day 30 defined as (i) admission clinical symptom resolved (ii) admission | — |
Countries
France
Contacts
Public ContactProject Manager
APHP
Outcome results
None listed