Antibioprophylaxis for Excision-graft Surgery in Burn Patient (A2B-TRIAL)

Study Overview
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Brief Summary
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The indication of antibiotic prophylaxis in burn patients remains highly controversial and hasn't reached a consensus. The objective of antibiotic prophylaxis would be to reduce the risk of post-operative local and systemic infections. Burn surgery is associated with a high risk of bacteremia and postoperative infections and sepsis. However, antibiotic prophylaxis exposes to the risk of selecting drug-resistant pathogens as well as adverse effects of antibiotics (i.e Clostridium difficile colitis). Recommendations regarding perioperative prophylaxis using systemic antibiotics vary across sources. The lack of data precludes any international strong recommendations regarding the best strategy regarding antibiotic prophylaxis. The goal of this project is therefore to determine whether peri-operative systemic antibiotics prophylaxis could reduce the incidence of post-operative infections in burn patients.

Detailed Description
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The intensive care unit investigator will verify the inclusion and non-inclusion criteria. The following parameters will be collected at ICU/burn centers: Hemodynamic parameters; sepsis organ failure assessment (SOFA) score, Glasgow Coma scale; Medical history / comorbidities; Concomitant treatment; Burn wound bacterial colonization; Biological parameters. The inclusion and randomization will be performed as late as possible before the first surgical procedure. Randomization: Burn patients with deep burn between 5 to 40% TBSA requiring at least one excision surgery graft will be randomized to receive antibioprophylaxis (or placebo) 30 minutes before the incision with either first generation cephalosporin (cefazolin) (if absence of colonization to Pseudomonas aeruginosa); or piperacillin-tazobactam (if the burned area is colonized with Pseudomonas aeruginosa). We chose to target specifically Pseudomonas aeruginosa because it has been associated with significant morbidity and risk of graft lysis in burn patients. No specific exams are required during the 7 days, 28 days and 90 days follow up visits. The end of research visit is the 90-day follow-up visit. If the patient has been discharged from the hospital, the 90-day visit will consist of a telephone contact with the patient if he or she has been discharged home or with the medical team of the healthcare structure if the patient has been discharged to another structure.

Official Title
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Antibioprophylaxis for Excision-graft Surgery in Burn Patient: a Multicenter Randomized Double-blind Study: A2B Trial

Conditions
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Burns Surgery

Intervention / Treatment
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* Drug: active intervention
* Other: placebo intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient over 18 years and less than 80 years old Burned patients requiring at least one excision-graft surgery Burn TBSA% between 5% and 40% Signed informed consent or inclusion under the emergency provisions of the law (article L1122-1-2 of the CSP) Exclusion Criteria: Proven severe allergy to cephalosporin or piperacilline-tazobactam or any other antibacterial agent of the penicillin class History of severe allergic reaction to any other beta-lactam (eg cephalosporins, monobactams or carbapenems) Patient on antibiotic therapy at the time of inclusion Pregnant or breast-feeding patient Patient not covered by the social security Patient transferred from another burn Unit Patient participant in investigational competitive medicinal product study on the primary endpoint Patient with local or systemic signs of infection requiring systemic antimicrobial therapy Patient under guardian ship Patient under curatorship Known colonization of the burned area to be excised with tazocillin-resistant germ. Obese patient

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Double-blind, randomized controlled study with two arms (1:1) Arm 1 : With antibiotic prophylaxis strategy, (cefazolin) if absence of colonization to Pseudomonas aeruginosa; or (piperacilline-tazobactam) if the burn is colonized with Pseudomonas aeruginosa. Arm 2 : Without antibiotic prophylaxis strategy (placebo)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: active group<br>The antibiotic prophylaxis will be cefazolin 2 g powder for solution for injection diluted in 50mL of NaCl 0.9%, IV infusion on 30 minutes with syringe pump, in case of absence of colonization to Pseudomonas aeruginosa prior to the surgical procedure. The dose administer is 2g. Antibiotic prophylaxis will be piperacilline-tazobactam 4 g powder for solution for injection diluted in 50mL of NaCl 0.9%, IV infusion on 30 minutes with syringe driver in patients with burn wound colonized to Pseudomonas aeruginosa. The dose administer is 4g. | Drug: active intervention<br>* The antibiotic prophylaxis will be cefazolin 2 g, or piperacilline-tazobactam 4 g, powder for solution for injection diluted in 50mL of NaCl 0.9%, IV infusion on 30 minutes with syringe pump.<br>* Other names: Cefazolin or piperacilline-tazobactam 4 g;|
| Placebo Comparator: Placebo group<br>The control group will received, as placebo NaCl 0.9% solution for injection diluted in 50mL of NaCl 0.9%, IV infusion on 30 minutes with syringe pump. | Other: placebo intervention<br>* The control group will received, as placebo NaCl 0.9% solution for injection diluted in 50mL of NaCl 0.9%, IV infusion on 30 minutes with syringe pump.<br>* Other names: NaC 0,9%l;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post-operative infection defined as Post-operative sepsis and/or Surgical site infection, and/or Graft lysis requiring a new graft within 7 days after surgery. | Postoperative infection will be collected by the intensivists or infectious disease specialist consultant blinded to the interventional or control arm. Skin infection and skin graft lysis requiring a new graft procedure will be assess by a surgeon blinded of the arm of the study. | 7 days after surgery | 
| Post-operative sepsis | Sepsis is defined as life-threatening organ dysfunction (defined by an increase of Sepsis related organ failure assessment [SOFA] score of 2 points or more) in response to infection. The minimum value is 0 and maximum value is 24. 0 meaning no organ dysfunction and 24 the maximum organ dysfunction. | 7 days after surgery | 
| Surgical site infection | Surgical site (operated skin) infection with general signs is considered as a systemic infection originated from skin (Presence of a local or loco-regional inflammatory reaction; Unfavourable and unexpected local evolution; Lysis of grafts; Necrosis of fat located under the graft) | 7 days after surgery | 
| Graft lysis needing a new graft procedure | Graft lysis is defined as a skin graft lysis in the 7 days post operative, and needing a new skin graft assessed be a surgeon blinded of the randomization group. | 7 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Any death occurring between randomization and D 90 | At day 90 | 
| Skin graft lysis requiring a new graft procedure | Defined as a skin graft lysis in the 7 days post operative, and needing a new skin graft assessed be a surgeon blinded of the randomization group. | 7 days after surgery | 
| Postoperative bacteremia | Positive blood culture . | within 7 days of surgery | 
| Post-operative pulmonary infection | Imaging Test Evidence Two or more serial chest imaging test results with at least one of the following: New and persistent or Progressive and persistent Infiltrate Consolidation Cavitation Signs/Symptoms/Laboratory For ANY PATIENT, at least one of the following: Fever (>38.0°C or >100.4°F) Leukopenia (≤4000 WBC/mm) or leukocytosis (>12,000 WBC/mm) For adults >70 years old, altered mental status with no other recognized cause And at least two of the following: New onset of purulent sputum or change in character of sputum, or increased respiratory secretions, or increased suctioning requirements New onset or worsening cough, or dyspnea, or tachypnea Rales or bronchial breath sounds Worsening gas exchange | 7 days after surgery | 
| Post-operative surgical site infection | Skin infection with general signs is considered as a systemic infection originated from skin. | 7 days after surgery | 
| Number of hospitalization days living without antibiotic therapy | It will be calculated as the number of survival days without antibiotic therapy respectively between randomization and day 28 and day 90. | at Day 28 and Day 90 | 
| Number of days of hospitalization until complete healing (> 95% total burn surface area) | It will be calculated by the number of days between ICU complete healing and ICU discharge. | at Day 28 and Day 90 | 
| Number of patients with a colonization with a multidrug resistant bacteria. | It will be defined as : AmpC producer enterobacteriacae Extended spectrum beta lactamase enterobacteriacae Carbapenemase producer enterobacteriacae Meticillin resistant aureus staphylococcus Vancomycine resistant enterococcus Piperacillin-Tazobactam resistant bacteria Imipenem resistant Acinetobacter Baumanii. And it will be mesured from results of bacterial cultures and/or genotyping with antibiogramm resistance profile | at Day 28 and Day 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antibioprophylaxis, sepsis, infection, graft lysis