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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Beta-lactam Intermittent Versus Continuous Infusion and Combination Antibiotic Therapy in Sepsis

Conditions
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Sepsis

Intervention / Treatment
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* Drug: continuous pivotal βL-AB
* Drug: intermittent pivotal βL-AB
* Drug: AG infusion most 1 dose
* Drug: AG infusion for 5 days


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: continuous infusion dosing of a pivotal AND AG infusion for 5 days<br>continuous infusion dosing of a pivotal βL-AB (CID group) AND AG infusion for 5 days (long duration) as appropriate combination therapy (ACT group) | Drug: continuous pivotal βL-AB<br>* continuous pivotal βL-AB<br>* Other names: CID group;Drug: AG infusion for 5 days<br>* AG infusion for 5 days (ACT Group)<br>* Other names: ACT Group;|
| Experimental: intermittent infusion dosing of a pivotal βL-AB ND AG infusion for 5 days<br>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) | Drug: intermittent pivotal βL-AB<br>* intermittent pivotal βL-AB (IID = control group)<br>* Other names: IID control group;Drug: AG infusion for 5 days<br>* AG infusion for 5 days (ACT Group)<br>* Other names: ACT Group;|
| Experimental: continuous infusion dosing of a pivotal βL-AB AND AG infusion at most 1 dose<br>continuous infusion dosing of a pivotal βL-AB (CID group) AND AG infusion at most 1 dose (AMT group ) | Drug: continuous pivotal βL-AB<br>* continuous pivotal βL-AB<br>* Other names: CID group;Drug: AG infusion most 1 dose<br>* AG infusion most 1 dose (AMT group )<br>* Other names: AMT group;|
| Experimental: intermittent infusion dosing of a pivotal βL-AB AND AG infusion at most 1 dose<br>intermittent infusion dosing of a pivotal βL-AB (IID = group) AND AG infusion at most 1 dose (AMT group) | Drug: intermittent pivotal βL-AB<br>* intermittent pivotal βL-AB (IID = control group)<br>* Other names: IID control group;Drug: AG infusion most 1 dose<br>* AG infusion most 1 dose (AMT group )<br>* Other names: AMT group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the 30-day mortality of patients with hospital-acquired sepsis in the ICU | 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). | 30 days after acquiring sepsis | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| New carriage, colonization or infection with one of the following BMR-GNB: at days 3, 7 and 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; | days 3,7and 30 | 
| 30 day mortality in patient with proven Gram-negative infection | Mortality rate at day 30 in patients with proven GNI | 30 days after inclusion | 
| 30 day mortality in patient with proven non-fermentative GNI | Mortality rate at day 30 in patients with proven non-fermentative GNI, | 30 days after inclusion | 
| 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). | 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 days after inclusion | 
| 30-day mortality in patients that received non-carbapenem-βL | Mortality rate at day 30 in patients that received non-carbapenem-βL | 30 days after inclusion | 
| 30-day clinical recovery | Clinical recovery at day 30 defined as admission clinical symptom resolved | 30 days after inclusion | 
| 30-day clinical recovery | Clinical recovery at day 30 defined as admission organ failures resolved with persistence of admission clinical symptoms and time to clinical recovery | 30 days after inclusion | 
| PK-PD (pharmacokinetic-pharmacodynamic) target attainment | PK-PD target attainment rate evaluated as a dichotomous variable o For βL (trough or plateau concentration according to randomization group), at day 1, i.e. 24 hours after the loading dose and at day 3, i.e. 72 hours after the loading dose § Target attainment scored Yes if measured drug concentration exceeded greater than four times to the causative pathogen MIC as 100% fT > 4*MIC | at day 1, i.e. 24 hours after the loading dose and at day 3, i.e. 72 hours after the loading dose | 
| PK-PD (pharmacokinetic-pharmacodynamic) target attainment | 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 > 12 | 30 min after the end of the first infusion dose (CMAX) | 
| Superinfection (primary infection site) or new infection (different infection site) at day 30 due to a GNB resistant to the βL administered at inclusion | Percentage of patients with superinfection or new nosocomial infection with GNB resistant to the βL administered at inclusion until day 30 | 30 days after inclusion | 
| Microbiological failure persistence of the same microorganism at the same site at end-of-therapy (EOT) or within 7 days after EOT. | 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 | 7 days after inclusion | 
| New carriage, colonization or infection with Pseudomonas aeruginosa not susceptible to the βL administered at days 3, 7 and 30 | Percentage of patients with new carriage colonization or infection with Pseudomonas aeruginosa not susceptible to the βL administered until day 30 | 30 days after inclusion | 
| Duration of organ failure between day 1 and day 30 | Organ failures assessed by AUCSOFA and its organ components measured between day 1 and day 30 | day 1 and day 30 | 
| Length of ICU and hospital stays | Length of ICU and hospital stays until day 30 | 30 days after inclusion | 
| Occurrence of adverse events at day 30 | 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 | 30 days after inclusion | 
| 180-day mortality | Mortality rate at day 180 | 180 days after inclusion |