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

Overview

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.

Interventions

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

Primary outcome measures

• To compare the 30-day mortality of patients with hospital-acquired sepsis in the ICU [Time frame: 30 days after acquiring sepsis]

Secondary outcome measures (12)

• New carriage, colonization or infection with one of the following BMR-GNB: at days 3, 7 and 30: [Time frame: days 3,7and 30]
• 30 day mortality in patient with proven Gram-negative infection [Time frame: 30 days after inclusion]
• 30 day mortality in patient with proven non-fermentative GNI [Time frame: 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). [Time frame: 30 days after inclusion]
• 30-day mortality in patients that received non-carbapenem-βL [Time frame: 30 days after inclusion]
• 30-day clinical recovery [Time frame: 30 days after inclusion]
• 30-day clinical recovery [Time frame: 30 days after inclusion]
• PK-PD (pharmacokinetic-pharmacodynamic) target attainment [Time frame: 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 [Time frame: 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 [Time frame: 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. [Time frame: 7 days after inclusion]
• New carriage, colonization or infection with Pseudomonas aeruginosa not susceptible to the βL administered at days 3, 7 and 30 [Time frame: 30 days after inclusion]

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)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

France · 28 centers

• Médecine intensive - réanimation - CHU Amiens-Picardie — Amiens
• Réanimation polyvalente - CH d'Argenteuil - Hôpital Victor Dupuy — Argenteuil
• Réanimation polyvalente - CH Avignon — Avignon
• Médecine intensive - réanimation - CHU Bordeaux - Hôpital Pellegrin — Bordeaux
• Médecine intensive - réanimation - Ambroise Paré — Boulogne-Billancourt
• Médecine intensive - réanimation - CHU Gabriel Montpied — Clermont-Ferrand
• Anesthésie - Réanimation - Beaujon — Clichy
• Réanimation polyvalente/Surveillance continue - CH Sud Essonne-Etampes — Étampes
• … and 20 more centers

Identifiers

NCT: NCT05681442 · APHP180596

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗