Clinical trial NCT05681442: Beta-lactam Intermittent Versus Continuous Infusion and Combination Antibiotic Therapy in Sepsis
Official title: Beta-lactam Intermittent Versus Continuous Infusion and Combination Antibiotic Therapy in Sepsis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Sepsis
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2023-01-12
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model 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
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* Adults (≥ 18 years)
* Hospital-acquired sepsis (according to sepsis 3.0 definitions) :

  * Patient hospitalized for more than 48 hours OR Patient discharged less than 48 hours ago
  * AND sepsis diagnosed within the last 24 hours
* 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 3 months prior to sepsis onset Prolonged mechanical ventilation (≥ 5 days on mechanical ventilation) within 3 months 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 within 3 months prior to sepsis onset
  * Exposure to an antibiotic (amoxicillin-clavulanic acid, C2G, C3G, fluoroquinolones) within 3 months prior to sepsis onset
  * A trip abroad to known geographical areas at risk (in particular the Indian subcontinent, South-East Asia, the Middle East and North Africa, the Mediterranean Basin) within 3 months prior to sepsis onset
  * 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

Exclusion Criteria:

* 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 ceftazidime, piperacillin-tazobactam, cefepime, meropenem, ceftazidime-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 (corresponding to a positive ECBU not responsible for sepsis)
* 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 therapyfor the new sepsis before randomisation: (\> 2 doses of antibiotics or \> 16h for continuous infusion
* Limitation of life support (comfort care applied only) at the time of screening
* Enrolment to another interventional drug 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)

Primary outcomes:
measure: To compare the 30-day mortality of patients with hospital-acquired sepsis in the ICU
timeFrame: 30 days after acquiring sepsis
Secondary outcomes:
measure: New carriage, colonization or infection with one of the following BMR-GNB: at days 3, 7 and 30:
timeFrame: days 3,7and 30
measure: 30 day mortality in patient with proven Gram-negative infection
timeFrame: 30 days after inclusion
measure: 30 day mortality in patient with proven non-fermentative GNI
timeFrame: 30 days after inclusion
measure: 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).
timeFrame: 30 days after inclusion
measure: 30-day mortality in patients that received non-carbapenem-βL
timeFrame: 30 days after inclusion
measure: 30-day clinical recovery
timeFrame: 30 days after inclusion
measure: 30-day clinical recovery
timeFrame: 30 days after inclusion
measure: PK-PD (pharmacokinetic-pharmacodynamic) target attainment
timeFrame: at day 1, i.e. 24 hours after the loading dose and at day 3, i.e. 72 hours after the loading dose
measure: PK-PD (pharmacokinetic-pharmacodynamic) target attainment
timeFrame: 30 min after the end of the first infusion dose (CMAX)
measure: Superinfection (primary infection site) or new infection (different infection site) at day 30 due to a GNB resistant to the βL administered at inclusion
timeFrame: 30 days after inclusion
measure: Microbiological failure persistence of the same microorganism at the same site at end-of-therapy (EOT) or within 7 days after EOT.
timeFrame: 7 days after inclusion
measure: New carriage, colonization or infection with Pseudomonas aeruginosa not susceptible to the βL administered at days 3, 7 and 30
timeFrame: 30 days after inclusion
measure: Duration of organ failure between day 1 and day 30
timeFrame: day 1 and day 30
measure: Length of ICU and hospital stays
timeFrame: 30 days after inclusion
measure: Occurrence of adverse events at day 30
timeFrame: 30 days after inclusion
measure: 180-day mortality
timeFrame: 180 days after inclusion
Other outcomes:
Locations:
city: Amiens
country: France
facility: Médecine intensive - réanimation - CHU Amiens-Picardie
city: Argenteuil
country: France
facility: Réanimation polyvalente - CH d'Argenteuil - Hôpital Victor Dupuy
city: Avignon
country: France
facility: Réanimation polyvalente - CH Avignon
city: Bordeaux
country: France
facility: Médecine intensive - réanimation - CHU Bordeaux - Hôpital Pellegrin
city: Boulogne-Billancourt
country: France
facility: Médecine intensive - réanimation - Ambroise Paré
city: Clermont-Ferrand
country: France
facility: Médecine intensive - réanimation - CHU Gabriel Montpied
city: Clichy
country: France
facility: Anesthésie - Réanimation - Beaujon
city: La Roche-sur-Yon
country: France
facility: Médecine intensive - réanimation-Centre Hospitalier Départemental Vendée
city: La Tronche
country: France
facility: Médecine intensive - réanimation - CHU Grenoble-Alpes Hôpital Michallon
city: Le Chesnay
country: France
facility: Réanimation polyvalente - CH de Versailles - Hôpital André Mignot
city: Le Mans
country: France
facility: Réanimation Médico Chirurgicale & USC - CH Le Mans
city: Lyon
country: France
facility: Médecine Intensive Réanimation - Hôpital Croix Rousse
city: Lyon
country: France
facility: Médecine intensive - réanimation - HCL - Edouard Herriot
city: Metz
country: France
facility: Réanimation polyvalente - CHR Metz-Thionville - Hôpital de Mercy
city: Montpellier
country: France
facility: Médecine intensive - réanimation - CHU Montpellier - Hôpital Lapeyronie
city: Montpellier
country: France
facility: Réanimation Chirurgicale - Saint Eloi
city: Nice
country: France
facility: Médecine Intensive Réanimation - Pasteur 2
city: Nice
country: France
facility: Médecine intensive - réanimation - CHU Nice - Hôpital Archet
city: Orléans
country: France
facility: Médecine intensive - réanimation
city: Paris
country: France
facility: Médecine intensive et réanimation infectieuse - Bichat
city: Paris
country: France
facility: Réanimation chirurgicale - Bichat
city: Poitiers
country: France
facility: Anesthésie - Réanimation - CHU Poitiers - Site de la Milétrie
city: Poitiers
country: France
facility: Médecine intensive - réanimation - CHU Poitiers - Site de la Milétrie
city: Reims
country: France
facility: Médecine intensive et réanimation polyvalente 6 CHU de Reims - Hôpital Robert Debré
city: Saint-Denis
country: France
facility: Médecine intensive - réanimation-CH St Denis - Hôpital Delafontaine
city: Strasbourg
country: France
facility: Médecine intensive - réanimation - CHU de Strasbourg - Nouvel Hôpital Civil
city: Étampes
country: France
facility: Réanimation polyvalente/Surveillance continue - CH Sud Essonne-Etampes
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris (AP-HP)
name: Aline DECHANET
role: STUDY_CHAIR
References: