Beta-lactam Intermittent Versus Continuous Infusion and Combination Antibiotic Therapy in Sepsis
- Conditions
- Sepsis
- Interventions
- Drug: intermittent pivotal βL-ABDrug: continuous pivotal βL-ABDrug: AG infusion most 1 doseDrug: AG infusion for 5 days
- Registration Number
- NCT05681442
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- Brief Summary
Patients hospitalized in ICU with sepsis (infection with life-threatening organ dysfunction according to sepsis 3.0 definitions) or septic shock presumably due to MDR-GNB (multidrug resistant Gram-negative bacteria). The study will be a prospective multicentre, randomized, open-label comparative continuous vs. intermittent pivotal βL (Beta Lactamine) antibiotic infusion strategies and combination vs. monotherapy trial conducted with a 2X2 factorial design.
- Detailed Description
The study will be a prospective multicentre, randomized, open-label comparative continuous vs. intermittent pivotal βL antibiotic infusion strategies and combination vs. monotherapy trial conducted with a 2X2 factorial design.
Patients will be randomized to one of four of the following treatment groups in a 1:1:1:1 ratio. Randomization will be stratified on the centre and the initial βL administered (meropenem versus other) to receive (i) βL antibiotic either as a continuous infusion: CID group or as intermittent infusion: IID group, and (ii) either at most 1 dose (short duration) : AMT group or 5 days (long duration) : ACT group of aminoglycoside
* Arm A: continuous infusion dosing of a pivotal βL-AB (Antibiotics) (CID group) AND AG (Aminoglycoside) infusion for 5 days (long duration) as appropriate combination therapy (ACT group)
* Arm B: intermittent infusion dosing of a pivotal βL-AB (IID = control group) AND AG infusion for 5 days (long duration) as appropriate combination therapy (ACT = group)
* Arm C: continuous infusion dosing of a pivotal βL-AB (CID group) AND AG infusion at most 1 dose (AMT group)
* Arm D: intermittent infusion dosing of a pivotal βL-AB (IID = group) AND AG infusion at most 1 dose (AMT group)
The primary objective of the study is to compare the 30-day mortality of patients with hospital-acquired sepsis in the ICU according to the mode of administration of the pivotal βL antibiotic (CID group vs. IID group).
The primary endpoint is the mortality rate at day 30 between CID and IID groups while the Co-primary objective is to compare the MAKE 30 (Major Adverse Kidney Events within 30 days) between patients that will receive an appropriate monotherapy with βL (AMT group) or an appropriate combination therapy with βL and 5 days of AG (ACT group).
moreover, 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 600
-
Adults (≥ 18 years)
-
Hospital-acquired sepsis or septic shock diagnosed in the past 24 hours (according to sepsis 3.0 definitions)
-
One of the following risk factors for gram negative 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
- Exposure to an antibiotic (amoxicillin-clavulanic acid, C2G, C3G, fluoroquinolones) in the previous 3 months
- A trip abroad within 3 months to known geographical areas at risk (in particular the Indian subcontinent, South-East Asia, the Middle East and North Africa, the Mediterranean Basin)
- A functional or organic abnormality of the urinary tract in case of urinary tract infection.
-
Appropriate bacteriological sampling performed before starting antimicrobial therapy
-
Expected stay in ICU of more than 3 days
- A priori known resistance to all the proposed beta-lactams or to amikacin Need for extrarenal treatment at inclusion according to the criteria of Gaudry et al.
- Known hypersensitivity to ceftazidim, piperacillin-tazobactam, cefepim, meropenem, ceftazidim-avibactam, ceftazolane-avibactam or to any of the excipients included in the corresponding pharmaceutical drugs,
- Known hypersensitivity to any cephalosporin antibacterial agent,
- Know hypersentitivity to any penem antibacterial agent,
- Severe known hypersensitivity (eg, anaphylactic reaction, severe skin reaction) to any other beta-lactam antibiotic (eg, penicillins or monobactam ) or to any of its excipients.
- Known contraindication to the aminoglycoside family including
- Hypersensitivity to the active substance, to any aminoglycoside antibacterial agent or to any of the excipients included in the corresponding pharmaceutical drugs,
- Cirrhosis of grades B and C according to the Child-Pugh classification.
- Myasthenia gravis.
- Simultaneous administration of another aminoglycoside
- Association with ataluren
- Non-complicated urinary tract infection (with the exception of acute prostatitis)
- Bone marrow transplant or chemotherapy-induced neutropenia
- 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
- Presence of antibiotic therapy for the new sepsis (if sepsis acquired in the hospital outside the resuscitation> 2 doses of antibiotics)
- Hospitalization in a short stay hospital of more than 48 hours
- Limitation of life support (comfort care applied only) at the time of screening
- Enrolment to another interventional study
- Pregnancy or breastfeeding
- Subject deprived of freedom, subject under a legal protective measure
- Non affiliation to any health insurance system
- Refusal to participate to the study (patient or legal representative or family member or close relative if present)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description intermittent infusion dosing of a pivotal βL-AB AND AG infusion at most 1 dose intermittent pivotal βL-AB intermittent infusion dosing of a pivotal βL-AB (IID = group) AND AG infusion at most 1 dose (AMT group) intermittent infusion dosing of a pivotal βL-AB AND AG infusion at most 1 dose AG infusion most 1 dose intermittent infusion dosing of a pivotal βL-AB (IID = group) AND AG infusion at most 1 dose (AMT group) continuous infusion dosing of a pivotal βL-AB AND AG infusion at most 1 dose continuous pivotal βL-AB continuous infusion dosing of a pivotal βL-AB (CID group) AND AG infusion at most 1 dose (AMT group ) continuous infusion dosing of a pivotal AND AG infusion for 5 days continuous pivotal βL-AB continuous infusion dosing of a pivotal βL-AB (CID group) AND AG infusion for 5 days (long duration) as appropriate combination therapy (ACT group) continuous infusion dosing of a pivotal AND AG infusion for 5 days AG infusion for 5 days continuous infusion dosing of a pivotal βL-AB (CID group) AND AG infusion for 5 days (long duration) as appropriate combination therapy (ACT group) intermittent infusion dosing of a pivotal βL-AB ND AG infusion for 5 days intermittent pivotal βL-AB intermittent infusion dosing of a pivotal βL-AB (IID = control group) AND AG infusion for 5 days (long duration) as appropriate combination therapy (ACT = group) intermittent infusion dosing of a pivotal βL-AB ND AG infusion for 5 days AG infusion for 5 days intermittent infusion dosing of a pivotal βL-AB (IID = control group) AND AG infusion for 5 days (long duration) as appropriate combination therapy (ACT = group) continuous infusion dosing of a pivotal βL-AB AND AG infusion at most 1 dose AG infusion most 1 dose continuous infusion dosing of a pivotal βL-AB (CID group) AND AG infusion at most 1 dose (AMT group )
- Primary Outcome Measures
Name Time Method To compare the 30-day mortality of patients with hospital-acquired sepsis in the ICU 30 days after acquiring sepsis the primary objective is to compare the 30-day mortality of patients with hospital-acquired sepsis in the ICU according to the mode of administration of the pivotal βL antibiotic (CID group vs. IID group).
- Secondary Outcome Measures
Name Time Method New carriage, colonization or infection with one of the following BMR-GNB: at days 3, 7 and 30: days 3,7and 30 Percentage of patients with new carriage of MDR-GNB(taking into account all clinical samples and rectal surveillance swabs performed routinely each week),i.e one of the following ticarcillin-resistant Pseudomonas aeruginosa,Acinetobacter baumannii,or Stenotrophomonas maltophilia; extended-spectrum β-lactam-producing Entero bacteriaceae;high-concentration cephalosporinase producing AmpC Enterobacteriaceae;
30 day mortality in patient with proven non-fermentative GNI 30 days after inclusion Mortality rate at day 30 in patients with proven non-fermentative GNI,
Microbiological failure persistence of the same microorganism at the same site at end-of-therapy (EOT) or within 7 days after EOT. 7 days after inclusion Percentage of patients for whom the microorganism is still recovered in bacterial culture from the initial infected site at EOT or within 7 days after EOT
Duration of organ failure between day 1 and day 30 day 1 and day 30 Organ failures assessed by AUCSOFA and its organ components measured between day 1 and day 30
30-day mortality in patients that received non-carbapenem-βL 30 days after inclusion Mortality rate at day 30 in patients that received non-carbapenem-βL
PK-PD (pharmacokinetic-pharmacodynamic) target attainment 30 min after the end of the first infusion dose (CMAX) For AG, 30 min after the end of the first infusion dose (CMAX)
§ Target attainment scored "Yes" if measured drug concentration to causative pathogen MIC ratio is greater than 12 as CMAX/MIC \> 12Superinfection (primary infection site) or new infection (different infection site) at day 30 due to a GNB resistant to the βL administered at inclusion 30 days after inclusion Percentage of patients with superinfection or new nosocomial infection with GNB resistant to the βL administered at inclusion until day 30
New carriage, colonization or infection with Pseudomonas aeruginosa not susceptible to the βL administered at days 3, 7 and 30 30 days after inclusion Percentage of patients with new carriage colonization or infection with Pseudomonas aeruginosa not susceptible to the βL administered until day 30
Length of ICU and hospital stays 30 days after inclusion Length of ICU and hospital stays until day 30
180-day mortality 180 days after inclusion Mortality rate at day 180
30 day mortality in patient with proven Gram-negative infection 30 days after inclusion Mortality rate at day 30 in patients with proven GNI
30 day mortality in patient with proven GNI for which the minimum inhibitory concentration (MIC) of the βL used were higher to the breakpoints according to the European committee on Antimicrobial Susceptibility Testing (EUCAST). 30 days after inclusion Mortality rate at day 30 in patients with proven GNI for which the MIC of the βL used were higher to the accepted break-points
30-day clinical recovery 30 days after inclusion Clinical recovery at day 30 defined as admission organ failures resolved with persistence of admission clinical symptoms and time to clinical recovery
Occurrence of adverse events at day 30 30 days after inclusion Percentage of patients with encephalopathy (delay between inclusion and 2 RASS scores = -1 in a row) or renal failure at discharge (RRT or persistent renal dysfunction) until day 30
Trial Locations
- Locations (27)
Médecine Intensive Réanimation - Hôpital Croix Rousse
🇫🇷Lyon, France
Réanimation Chirurgicale - Saint Eloi
🇫🇷Montpellier, France
Médecine Intensive Réanimation - Pasteur 2
🇫🇷Nice, France
Médecine intensive - réanimation
🇫🇷Orléans, France
Médecine intensive - réanimation - CHU Amiens-Picardie
🇫🇷Amiens, France
Réanimation polyvalente - CH d'Argenteuil - Hôpital Victor Dupuy
🇫🇷Argenteuil, France
Réanimation polyvalente - CH Avignon
🇫🇷Avignon, France
Médecine intensive - réanimation - CHU Bordeaux - Hôpital Pellegrin
🇫🇷Bordeaux, France
Médecine intensive - réanimation - Ambroise Paré
🇫🇷Boulogne-Billancourt, France
Médecine intensive - réanimation - CHU Gabriel Montpied
🇫🇷Clermont-Ferrand, France
Anesthésie - Réanimation - Beaujon
🇫🇷Clichy, France
Médecine intensive - réanimation-Centre Hospitalier Départemental Vendée
🇫🇷La Roche-sur-Yon, France
Médecine intensive - réanimation - CHU Grenoble-Alpes Hôpital Michallon
🇫🇷La Tronche, France
Réanimation polyvalente - CH de Versailles - Hôpital André Mignot
🇫🇷Le Chesnay, France
Réanimation Médico Chirurgicale & USC - CH Le Mans
🇫🇷Le Mans, France
Médecine intensive - réanimation - HCL - Edouard Herriot
🇫🇷Lyon, France
Réanimation polyvalente - CHR Metz-Thionville - Hôpital de Mercy
🇫🇷Metz, France
Médecine intensive - réanimation-CH St Denis - Hôpital Delafontaine
🇫🇷Saint-Denis, France
Médecine intensive - réanimation - CHU de Strasbourg - Nouvel Hôpital Civil
🇫🇷Strasbourg, France
Médecine intensive - réanimation - CHU Montpellier - Hôpital Lapeyronie
🇫🇷Montpellier, France
Médecine intensive - réanimation - CHU Nice - Hôpital Archet
🇫🇷Nice, France
Médecine intensive et réanimation infectieuse - Bichat
🇫🇷Paris, France
Réanimation chirurgicale - Bichat
🇫🇷Paris, France
Anesthésie - Réanimation - CHU Poitiers - Site de la Milétrie
🇫🇷Poitiers, France
Médecine intensive - réanimation - CHU Poitiers - Site de la Milétrie
🇫🇷Poitiers, France
Médecine intensive et réanimation polyvalente 6 CHU de Reims - Hôpital Robert Debré
🇫🇷Reims, France
Réanimation polyvalente/Surveillance continue - CH Sud Essonne-Etampes
🇫🇷Étampes, France