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

Sepsis Clinical Trial

— BICCS  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05681442
• Other study ID #: APHP180596
• Status: Recruiting
• Phase: Phase 4
• Start date: November 13, 2023
• Est. completion date: January 1, 2025

Study information

• Verified date: April 2024
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Jean-François TIMSIT, MD-PhD
• Phone: 01.40.25.77.07
• Email: jean-françois.timsit[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 600
• Est. completion date: January 1, 2025
• Est. primary completion date: September 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Sepsis
• Toxemia

Intervention

Drug:
• continuous pivotal ßL-AB
continuous pivotal ßL-AB
• intermittent pivotal ßL-AB
intermittent pivotal ßL-AB (IID = control group)
• AG infusion most 1 dose
AG infusion most 1 dose (AMT group )
• AG infusion for 5 days
AG infusion for 5 days (ACT Group)

Locations

Country	Name	City	State
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	Réanimation et soins continus - CH Béthune - Beuvry	Béthune
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	Réanimation polyvalente/Surveillance continue - CH Sud Essonne-Etampes	Étampes
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 - 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	Médecine intensive - réanimation-CH St Denis - Hôpital Delafontaine	Saint-Denis
France	Médecine intensive - réanimation - CHU de Strasbourg - Nouvel Hôpital Civil	Strasbourg

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 ßL antibiotic (CID group vs. IID group).	30 days after acquiring sepsis
Secondary	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 ß-lactam-producing Entero bacteriaceae;high-concentration cephalosporinase producing AmpC Enterobacteriaceae;	days 3,7and 30
Secondary	30 day mortality in patient with proven Gram-negative infection	Mortality rate at day 30 in patients with proven GNI	30 days after inclusion
Secondary	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
Secondary	30 day mortality in patient with proven GNI for which the minimum inhibitory concentration (MIC) of the ßL 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 ßL used were higher to the accepted break-points	30 days after inclusion
Secondary	30-day mortality in patients that received non-carbapenem-ßL	Mortality rate at day 30 in patients that received non-carbapenem-ßL	30 days after inclusion
Secondary	30-day clinical recovery	Clinical recovery at day 30 defined as admission clinical symptom resolved	30 days after inclusion
Secondary	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
Secondary	PK-PD (pharmacokinetic-pharmacodynamic) target attainment	PK-PD target attainment rate evaluated as a dichotomous variable; o For ßL (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
Secondary	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)
Secondary	Superinfection (primary infection site) or new infection (different infection site) at day 30 due to a GNB resistant to the ßL administered at inclusion	Percentage of patients with superinfection or new nosocomial infection with GNB resistant to the ßL administered at inclusion until day 30	30 days after inclusion
Secondary	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
Secondary	New carriage, colonization or infection with Pseudomonas aeruginosa not susceptible to the ßL administered at days 3, 7 and 30	Percentage of patients with new carriage colonization or infection with Pseudomonas aeruginosa not susceptible to the ßL administered until day 30	30 days after inclusion
Secondary	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
Secondary	Length of ICU and hospital stays	Length of ICU and hospital stays until day 30	30 days after inclusion
Secondary	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
Secondary	180-day mortality	Mortality rate at day 180	180 days after inclusion