Thank you for the introduction. Thank you to the organizer for the invitation and thank you to the Lancet to select my study to present today. It's a real honor to be here today to present the results of the Profi-Viper trial because it's a long history, 10 years of work for our team. The first grant was applied in 2013, the first patient included in the 2015, the last one in 2020 during COVID and the publication arrived two days ago in the Lancet Respiratory Medicine. So it's a long story and it was a great experience and it finished with this honorific presentation. So here are my disclosures. As all of you know, ventilator-associated pneumonia are the first cause of infection in ICU patients and comatose brain injured patients are particularly re-exposed to the early onset VAPs. VAPs increase morbid mortality, increase secondary insults in brain injured patients, it increases exposure to antibiotics, to mechanical ventilation, ICU and hospital stay and costs. That's why strategies to prevent VAP is very important and that's why international guidelines proposed several bundles to prevent VAPs. One of these prevention strategies associates STD to SOD, selective oropharyngeal decontamination and digestive tract decontamination during all the ICU stay of patients associated with short course of parenteral prophylactic antibiotics. Short course in the French guidelines means a maximum of five days of antibiotic which represent a long exposition to antibiotic finally. That's why in ICU teams in France and Europe we do not apply this widely, this recommendation because of the risk of emergence of antibiotic resistance pathogens. Everybody is quite fear about this recommendation. Another solution has been proposed and studied since two decades, it's a short prophylactic antibiotic without SDD and prophylactic antibodies in innate antibiotic or IV antibiotics. If we turn to in this maternalizes results to the IV antibiotics prophylactic strategies, the auto selected five studies and for the five studies were performed in brain injured patient and if we turn to the results, IV antibiotic seems to protect patient from VAPs with a relative risk of 0.46. Here are the four studies studied in this maternalizes, three of them were randomized trials, two of them with very little number of patient with no blind committed to review VAPs and the last one on the bottom was on cardiac arrest patient not on all type of brain injured patient. The only one with observational cohort was compared to an historical cohort and was showed a decreased incident of VAP after one dose of ceftriaxone. Recently another positive issue thanks to this center TBI cohort, here again antibiotics prophylaxis was reported to be an independent protective factor against VAP. To go further and to try to to show other benefits of these strategies, we perform the multi multi-center randomized double blind placebo control assessor mask trial in comatose brain injured patient within the atlantarea research network. Eight centers in this network, research network included patients and the main goal of the study was to assess efficacy of a single dose of two gram of ceftriaxone on prevention of early VAP. Secondary goals on day 28 was incidence of all type of VNP, bacteria induced VAP, antibiotic, mechanical ventilation exposure, ICU and hospital stay, neurological prognosis and mortality and safety. On day 60 you had ICU, hospital stay, neurological prognosis and mortality also. Patients who were eligible were adult comatose brain injured patient who needed more than 48 hours of mechanical ventilation and who were intubated for less than 12 hours. Exclusion criteria are listed here, patient with tumor, CNS infection, cardiac arrest who were intubated for more than 48 hours after hospitalization and hospitalization less than one month and ongoing treatment, antibiotic treatment, a predictable antibiotic prophylaxis, a predictable death at within the two-thirds day of admission after admission and the beta-lactam pathology. After inclusion and consent, patients were randomized to receive two grams of ceftriaxone or placebo within the 12 hours after tracheal intubation plus a bundle of VAP for VAP prevention except SDD. The primary outcome was a proportion of patients developing an early VAP, the diagnostic of VAP was defined according to the ATS definition except the threshold of the VAP with seven days and not five days and all VAPs were confirmed by a centralized blind committee, adjudication committee. The secondary outcomes were proportion of all type late onset VAP, the global VAP, number of ventilator free days or antibiotic free days, of ICU and hospital free days, type of micro-induced VAP, neurodegenerative prognosis with a modified ranking score, mortality and safety. 2,230 patients were eligible, we included, we randomized, sorry, to 345 patients, 165 patients in each group received allocated treatment, three with no consent in the ceftriaxone group and eight in the, in the placebo group and finally 162 patients in the ceftriaxone group was, were analyzed and 157 in the placebo group. Here are the population characteristics of the population, so 30% of patients were brain, trauma brain patient and the other was stroke or SAH. The majority of patients, so nearly 80% was severe comatose patient with a GCS less than 9 and the time, the median time to, from intubation to treatment was, was seven hours. 160 VAPs were declared by investigator and after adjudication committee, only 93 VAPs were confirmed by the blind adjudication committee. At least 28% of patients developed at least one VAP during their ICU, the 28th first day. Early VAPs were the majority of these VAP. If we turn to the primary outcome, a patient receiving a ceftriaxone were, were at lower risk for developing early VAP compared with those receiving placebo, with a decrease of incidence of the early VAP from 32% in placebo and to 14% in the ceftriaxone group. The same result for all VAP at day 28 with a decrease of incidence from 36% to 20% for all type of VAP. For the ventilator free days and antibiotic free days, they were significantly, significantly increased in the group, ceftriaxone group with an increase of four days for ventilating, for mechanical ventilation and six days for antibiotics. For the prognosis, ceftriaxone improved the prognosis of patient, especially thanks to mortality and with a decrease of mortality from 25% in the placebo group to 15% with a hazard ratio of 0.62. If we turn to the microbiological findings, the four more frequent bacteria isolated in our patient were, like in the literature previously published, meticillin sensitive staphylococcus aureus, streptococcus species, haemophilus influenzae and Escherichia coli. As you can see, the haemophilus influenzae was 33% in the placebo and 0% in the ceftriaxone group because of the spectrum of the ceftriaxone probably. And for the safety, three patients developed a clostridium difficile infection, one in ceftriaxone group and two in placebo group. And among the patient, the 115 patient with rectal swabs, ESBL-produxin anterobacteria acquisition was found in two patients with receiving ceftriaxone. For the outcome on day 60, the ceftriaxone increased the median ICU free days, the median hospital free days, but unfortunately, the mortality didn't reach a significance with a trend of the decrease of mortality from 30% to 20%, but it was not significantly different. So to conclude, PROFIVAB trials confirmed the protective effect of a single dose of two grams of ceftriaxone without application of the SDD in brain injured patient. It confirmed the protection of patients receiving ceftriaxone against early VAP, all types of VAP at day 28, antibiotic and mechanical ventilation exposition at day 28, mortality at day 28, and ICU and hospital exposure at day 60. I would like to thank all the investigators of the PROFIVAB trials for the study to have included during these five years patients. I would like to thank family of the patients who accepted to be involved, to involve their next of kin in this study. I would like to thank also the research team and the NCCU team where I work, and the research team FAR2, which are involved in research of pharmacology of antimicrobial agents and antibioresistance. Thank you for your attention.

Profi-Viper trial

ceftriaxone

ventilator-associated pneumonia

brain injury patients

ICU