Beta-lactam Intermittent Versus Continuous Infusion and Combination Antibiotic Therapy in Sepsis (BICCS)

Assistance Publique - Hôpitaux de Paris

Status and phase

Enrolling

Phase 4

Conditions

Sepsis

Treatments

Drug: intermittent pivotal βL-AB

Drug: AG infusion for 5 days

Drug: AG infusion most 1 dose

Drug: continuous pivotal βL-AB

Study type

Interventional

Funder types

Other

Identifiers

NCT05681442

APHP180596

Details and patient eligibility

About

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.

Full 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.

Enrollment

600 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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)

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

600 participants in 4 patient groups

continuous infusion dosing of a pivotal AND AG infusion for 5 days

Experimental group

Description:

continuous infusion dosing of a pivotal βL-AB (CID group) AND AG infusion for 5 days (long duration) as appropriate combination therapy (ACT group)

Treatment:

Drug: continuous pivotal βL-AB

Drug: AG infusion for 5 days

intermittent infusion dosing of a pivotal βL-AB ND AG infusion for 5 days

Experimental group

Description:

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)

Treatment:

Drug: AG infusion for 5 days

Drug: intermittent pivotal βL-AB

continuous infusion dosing of a pivotal βL-AB AND AG infusion at most 1 dose

Experimental group

Description:

continuous infusion dosing of a pivotal βL-AB (CID group) AND AG infusion at most 1 dose (AMT group )

Treatment:

Drug: continuous pivotal βL-AB

Drug: AG infusion most 1 dose

intermittent infusion dosing of a pivotal βL-AB AND AG infusion at most 1 dose

Experimental group