CEFEPIME HYDROCHLORIDE for Sepsis | Hospital-acquired sepsis

Inclusion criteria

• {"criterion_text":"- Adults (≥ 18 years)\n- Hospital-acquired sepsis (according to sepsis 3.0 definitions)\n- Patient hospitalized for more than 48 hours OR Patient discharged less than 48 hours ago\n- AND sepsis diagnosed within the last 24 hours\n- 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\n- Prolonged hospital stay (≥ 15 days of hospitalization) within 3 months prior to sepsis onset\n- Prolonged mechanical ventilation (≥ 5 days on mechanical ventilation) within 3 months prior to sepsis onset\n- Patients with indwelling devices (dialysis access lines, intravascular lines, urinary catheter, endotracheal or tracheostomy tube, gastrostomy or jejunostomy feeding tube)\n- Patients known to be infected, colonized or carriers of MDR gram negative bacteria within 3 months prior to sepsis onset\n- Exposure to an antibiotic (amoxicillin-clavulanic acid, C2G, C3G, fluoroquinolones) within 3 months prior to sepsis onset\n- 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\n- A functional or organic abnormality of the urinary tract in case of urinary tract infection.\n- Appropriate bacteriological sampling performed before starting antimicrobial therapy\n- Expected stay in ICU of more than 3 days"}

Exclusion criteria

• {"criterion_text":"- A priori known resistance to all the proposed beta-lactams or to amikacin\n- Need for extrarenal treatment at inclusion according to the criteria of Gaudry et al.\n- Known hypersensitivity to ceftazidime, piperacillin-tazobactam, cefepime, meropenem, ceftazidime-avibactam, ceftazolane-avibactam or to any of the excipients included in the corresponding pharmaceutical drugs\n- Known hypersensitivity to any cephalosporin antibacterial agent\n- Know hypersentitivity to any penem antibacterial agent\n- 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\n- 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\n- Cirrhosis of grades B and C according to the Child-Pugh classification\n- Myasthenia gravis\n- Simultaneous administration of another aminoglycoside\n- Association with ataluren\n- Non-complicated urinary tract infection (corresponding to a positive ECBU not responsible for sepsis)\n- Bone marrow transplant or chemotherapy-induced neutropenia\n- 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)\n- Presence of antibiotic therapy for the new sepsis (if sepsis acquired in the hospital outside the resuscitation> 2 doses of antibiotics or > 16h for continuous infusion)\n- Limitation of life support (comfort care applied only) at the time of screening\n- Enrolment to another interventional drug study\n- Pregnancy or breastfeeding\n- Subject deprived of freedom, subject under a legal protective measure\n- Non affiliation to any health insurance system\n- Refusal to participate to the study (patient or legal representative or family member or close relative if present)"}

Primary endpoints

• {"endpoint_text":"- The primary endpoint is the mortality rate at day 30 between CID and IID groups.","definition_or_measurement_approach":"Mortality rate at day 30 comparing CID (continuous infusion device) and IID (intermittent infusion device) groups."}

Secondary endpoints

• {"endpoint_text":"- 1.\tMortality rate at day 30 in patients with (i) proven GNI, (ii) proven non-fermentative GNI, (iii) proven GNI for which the MIC of the βL used were higher to the accepted break-points 2.\tMortality rate at day 30 in patients that received non-carbapenem-βL","definition_or_measurement_approach":"Mortality at day 30 measured in specified patient subgroups (proven Gram-negative infection, non-fermentative GNI, GNI with βL MIC above accepted breakpoints) and in patients receiving non-carbapenem beta-lactams."}
• {"endpoint_text":"- 3.\tClinical failure defined as meeting any of the following: a) Death either while on trial therapy or within 7 days following completion; b) Receipt of rescue therapy for the trial pathogen within 7 days of completion of trial treatment; c) Removal from the trial due to an adverse event considered related to trial treatment; d) Bacteremia more than 5 days after initiation of trial treatment with the same pathogen (if multiple pathogens at least one with the same AST);","definition_or_measurement_approach":"Clinical failure defined by listed criteria a–d (death during/within 7 days post-therapy, receipt of rescue therapy within 7 days, removal due to related AE, late bacteremia >5 days with same pathogen)."}
• {"endpoint_text":"- e) Improvement of shock (decrease by more than 50% of the initial norephrine dose or decrease by more at least 2 points of the SOFA score), within 7 days of completion of trial treatment; f) For patients with pneumonia: failure to improve or worsening of oxygenation by the end of trial treatment; g) For patients with intra-abdominal infections and urinary tract infections: need for re-intervention after more than 5 days of effective treatment or need for puncture debridement or sample from th","definition_or_measurement_approach":"Clinical improvement measures including shock improvement (≥50% norepinephrine dose reduction or ≥2-point SOFA decrease within 7 days), respiratory failure endpoints for pneumonia, and need for re-intervention for intra-abdominal/urinary infections."}
• {"endpoint_text":"- 4.\tPK-PD target attainment rate evaluated as a dichotomous variable o\tFor 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 \tTarget attainment scored “Yes” if measured drug concentration exceeded greater than four times to the causative pathogen MIC as 100% fT > 4*MIC","definition_or_measurement_approach":"PK-PD target attainment for beta-lactams at day 1 and day 3; 'Yes' if measured concentration >4× pathogen MIC for 100% fT."}
• {"endpoint_text":"- o\tFor AG, 30 min after the end of the first infusion dose (CMAX) \tTarget attainment scored “Yes” if measured drug concentration to causative pathogen MIC ratio is greater than 12 as CMAX/MIC > 12","definition_or_measurement_approach":"For aminoglycosides (AG), CMAX measured 30 min after first infusion; target attainment if CMAX/MIC > 12."}
• {"endpoint_text":"- 5.\tPercentage of patients with superinfection or new nosocomial infection with GNB resistant to the βL administered at inclusion until day 30 6.\t Percentage of patients with clinical failure for whom at least one of the microorganism responsible for the infection is still recovered in bacterial culture from the initial infected site at end-of-therapy (EOT) or within 7 days after EOT","definition_or_measurement_approach":"Proportion of patients with superinfection or new nosocomial GNB resistant to administered beta-lactam until day 30; proportion of clinical failures with persistent recovery of at least one causative microorganism at EOT or within 7 days post-EOT."}
• {"endpoint_text":"- 7.\tPercentage of patients with new carriage of MDR-GNB until day 30 (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;","definition_or_measurement_approach":"Percentage of patients with new carriage/colonization of specified multidrug-resistant Gram-negative bacteria up to day 30 using clinical samples and weekly rectal surveillance swabs."}
• {"endpoint_text":"- 8.\tPercentage of patients with new carriage colonization or infection with Pseudomonas aeruginosa not susceptible to the βL administered until day 30 9.\tOrgan failures assessed by AUCSOFA and its organ components measured between day 1 and day 30 10.\tPercentage of patients with encephalopathy (delay between inclusion and 2 RASS scores = -1 in a row) or renal failure at discharge until day 30 11.Length of ICU and hospital stays until day 30 12.Mortality rate at day 180","definition_or_measurement_approach":"Composite of microbiological and clinical outcomes: new Pseudomonas aeruginosa non-susceptibility up to day 30; organ failure metrics (AUCSOFA) day 1–30; encephalopathy/renal failure at discharge until day 30; ICU/hospital length of stay until day 30; mortality at day 180."}

France

Earliest CTIS Part Ii Submission Date

19-11-2024

Latest Decision Or Authorization Date

19-03-2026

Processing Time Days

485

Number Of Sites

25

Number Of Participants

600

Primary sponsor

Full Name

Assistance Publique Hopitaux De Paris

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France