Efficacy of Cotrimoxazole as a De-escalation Treatment of Ventilator-Associated Pneumonia in Intensive Care Unit

Multicentre randomized non-inferiority trial comparing cotrimoxazole to standard antibiotic therapy for enterobacterial VAP. Selection of patients will be done by physicians in ICU. All clinically suspected VAP will be confirmed with a lung sample (preferably bronchoalveolar lavage or protected distal specimen, otherwise endotracheal aspiration). Patients with a microbiologically confirmed VAP due to an Enterobacteriaceae susceptible to cotrimoxazole and at least one antibiotic of the empiric antibiotic therapy (based on international recommendations) will be included. After written informed consent, they will be randomized (1:1), using a computer-generated randomization scheme of various-sized blocks, stratified by presence of septic shock at VAP diagnosis and by presence of COVID-19 pneumonia on ICU admission, through a centralized 24 hours internet service (CleanWEB™) to cotrimoxazole, or best standard of care (either a beta-lactam or a fluoroquinolone), after randomization for a total duration of 7 days (including empiric initial appropriate treatment). Posology and modalities of antibiotic administration will be optimized based on most recent recommendations for ICU patients. Because antibiotic therapy will be variable in the control group, single or double blind is not appropriate. Daily follow-up until death or ICU discharge or day 28 will be performed (vital status, antibiotic therapy, new infection, Clostridium-difficile infection). Clinical (arterial blood gas, temperature, haematology, tracheal secretions) and radiological cure (chest X-ray) will be assessed at Day 7. Systematic MDR bacteria screening will be performed weekly and at ICU discharge. Vital status will be assessed at day 90. Alive patients leaving ICU before 90 days will be contacted by phone (if discharge at home) or by interview at hospital (if transferred in a different ward). Assessment of the clinical and radiological cure by an independent committee (1 specialist in infectious disease and 1 intensivist), blinded of the randomization arm (PROBE methodology).

• To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in term of mortality at day 90 [Time frame: 90 days after inclusion]
• To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in IC in terms of mechanical ventilation (MV)-free-days at day 28 [Time frame: 28 days after inclusion]
• To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of rate of cure between days 7 and 10 [Time frame: days 7 and 10 after inclusion]
• To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of VAP recurrence [Time frame: 28 days after inclusion]
• To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of ICU length of stay [Time frame: 28 days after inclusion]
• To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of hospital length of stay [Time frame: 28 days after inclusion]
• To assess the safety of cotrimoxazole compared to best standard of care at day 28 in terms of allergy to antibiotics [Time frame: 28 days after inclusion]
• To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of mortality at day 28 [Time frame: 28 days after inclusion]
• To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of overall antibiotic consumption [Time frame: day 28 after inclusion]
• To assess the ecological impact of the treatment in terms of acquisition of MDR bacteria in ICU [Time frame: 28 days after inclsuion]
• To assess the ecological impact of the treatment in terms of rate of Clostridioides difficile infection [Time frame: 28 days after inclusion]