BICCS: Beta-lactam Intermittent Versus Continuous Infusion and Combination Antibiotic Therapy in Sepsis
Study Details
Study Description
Brief Summary
Patients hospitalized in ICU with sepsis (infection with life-threatening organ dysfunction according to sepsis 3.0 definitions) 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
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
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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)
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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)
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Arm C: continuous infusion dosing of a pivotal βL-AB (CID group) AND AG infusion at most 1 dose (AMT group)
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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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: continuous infusion dosing of a pivotal AND 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) |
Drug: continuous pivotal βL-AB
continuous pivotal βL-AB
Other Names:
Drug: AG infusion for 5 days
AG infusion for 5 days (ACT Group)
Other Names:
|
| Experimental: intermittent infusion dosing of a pivotal βL-AB ND 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) |
Drug: intermittent pivotal βL-AB
intermittent pivotal βL-AB (IID = control group)
Other Names:
Drug: AG infusion for 5 days
AG infusion for 5 days (ACT Group)
Other Names:
|
| Experimental: continuous infusion dosing of a pivotal βL-AB AND AG infusion at most 1 dose continuous infusion dosing of a pivotal βL-AB (CID group) AND AG infusion at most 1 dose (AMT group ) |
Drug: continuous pivotal βL-AB
continuous pivotal βL-AB
Other Names:
Drug: AG infusion most 1 dose
AG infusion most 1 dose (AMT group )
Other Names:
|
| Experimental: intermittent infusion dosing of a pivotal βL-AB AND AG infusion at most 1 dose intermittent infusion dosing of a pivotal βL-AB (IID = group) AND AG infusion at most 1 dose (AMT group) |
Drug: intermittent pivotal βL-AB
intermittent pivotal βL-AB (IID = control group)
Other Names:
Drug: AG infusion most 1 dose
AG infusion most 1 dose (AMT group )
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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
- 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 Gram-negative infection [30 days after inclusion]
Mortality rate at day 30 in patients with proven GNI
- 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,
- 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 mortality in patients that received non-carbapenem-βL [30 days after inclusion]
Mortality rate at day 30 in patients that received non-carbapenem-βL
- 30-day clinical recovery [30 days after inclusion]
Clinical recovery at day 30 defined as admission clinical symptom resolved
- 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
- PK-PD (pharmacokinetic-pharmacodynamic) target attainment [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 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
- 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 > 12
- Superinfection (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
- 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
- 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
- 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
- Length of ICU and hospital stays [30 days after inclusion]
Length of ICU and hospital stays until day 30
- 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
- 180-day mortality [180 days after inclusion]
Mortality rate at day 180
Eligibility Criteria
Criteria
Inclusion Criteria:
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Adults (≥ 18 years)
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Hospital-acquired sepsis diagnosed in the past 24 hours (according to sepsis 3.0 definitions)
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One of the following risk factors for multidrug resistant pathogens :
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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
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Prolonged hospital stay (≥ 15 days of hospitalization) within 90 days prior to the occurrence of sepsis
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Prolonged mechanical ventilation (≥ 5 days on mechanical ventilation) within 90 days prior to sepsis onset
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Patients with indwelling devices (dialysis access lines, intravascular lines, urinary catheter, endotracheal or tracheostomy tube, gastrostomy or jejunostomy feeding tube)
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Patients known to be infected, colonized or carriers of MDR gram negative bacteria in the past 3 months
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Appropriate bacteriological sampling performed before starting antimicrobial therapy
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Expected stay in ICU of more than 3 days
Exclusion Criteria:
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Knowledge of the germ of inclusion infection resistant to all the proposed beta-lactams or resistant to amikacin
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Need for extrarenal treatment at inclusion according to the criteria of Gaudry et al.
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Known allergy to amikacin
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Known allergy to βL
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Non-complicated urinary tract infection (with the exception of acute prostatitis)
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Bone marrow transplant or chemotherapy-induced neutropenia
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Médecine intensive - réanimation - CHU Amiens-Picardie | Amiens | France | 80054 | |
| 2 | Réanimation polyvalente - CH d'Argenteuil - Hôpital Victor Dupuy | Argenteuil | France | 95100 | |
| 3 | Réanimation polyvalente - CH Avignon | Avignon | France | 84000 | |
| 4 | Médecine intensive - réanimation - CHU Bordeaux - Hôpital Pellegrin | Bordeaux | France | 33000 | |
| 5 | Médecine intensive - réanimation - Ambroise Paré | Boulogne-Billancourt | France | 92100 | |
| 6 | Réanimation et soins continus - CH Béthune - Beuvry | Béthune | France | 62660 | |
| 7 | Médecine intensive - réanimation - CHU Gabriel Montpied | Clermont-Ferrand | France | 63003 | |
| 8 | Anesthésie - Réanimation - Beaujon | Clichy | France | 92110 | |
| 9 | Médecine intensive - réanimation-Centre Hospitalier Départemental Vendée | La Roche-sur-Yon | France | 85000 | |
| 10 | Médecine intensive - réanimation - CHU Grenoble-Alpes Hôpital Michallon | La Tronche | France | 38700 | |
| 11 | Réanimation polyvalente - CH de Versailles - Hôpital André Mignot | Le Chesnay | France | 78150 | |
| 12 | Réanimation Médico Chirurgicale & USC - CH Le Mans | Le Mans | France | 72037 | |
| 13 | Médecine intensive - réanimation - HCL - Edouard Herriot | Lyon | France | 69437 | |
| 14 | Réanimation polyvalente - CHR Metz-Thionville - Hôpital de Mercy | Metz | France | 57085 | |
| 15 | Médecine intensive - réanimation - CHU Montpellier - Hôpital Lapeyronie | Montpellier | France | 34295 | |
| 16 | Médecine intensive - réanimation - CHU Nice - Hôpital Archet | Nice | France | 06202 | |
| 17 | Médecine intensive et réanimation infectieuse - Bichat | Paris | France | 75018 | |
| 18 | Réanimation chirurgicale - Bichat | Paris | France | 75018 | |
| 19 | Anesthésie - Réanimation - CHU Poitiers - Site de la Milétrie | Poitiers | France | 86000 | |
| 20 | Médecine intensive - réanimation - CHU Poitiers - Site de la Milétrie | Poitiers | France | 86000 | |
| 21 | Médecine intensive et réanimation polyvalente 6 CHU de Reims - Hôpital Robert Debré | Reims | France | 51100 | |
| 22 | Médecine intensive - réanimation-CH St Denis - Hôpital Delafontaine | Saint-Denis | France | 93200 | |
| 23 | Médecine intensive - réanimation - CHU de Strasbourg - Nouvel Hôpital Civil | Strasbourg | France | 67091 | |
| 24 | Réanimation polyvalente/Surveillance continue - CH Sud Essonne-Etampes | Étampes | France | 91150 |
Sponsors and Collaborators
- Assistance Publique - Hôpitaux de Paris
Investigators
- Study Chair: Aline DECHANET, Assistance Publique - Hôpitaux de Paris (AP-HP)
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- APHP180596