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

Phase 3

Recruiting

• Conditions: Ventilator Associated Pneumonia
• Interventions: Drug: cotrimoxazole; Drug: standard antibiotic therapy

• Registration Number: NCT05696093
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Brief Summary

Efficacy of cotrimoxazole as a de-escalation treatment for adult patients Ventilator-Associated Pneumonia in intensive care unit Multicentre randomized non-inferiority trial comparing cotrimoxazole to standard antibiotic therapy for enterobacterial VAP

Detailed Description

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).

Study Timeline

• Study First Submitted: 2022-11-21
• Study First Submitted QC: 2023-01-23
• Study First Posted: 2023-01-25
• Study Start: 2023-10-19
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-28
• Last Update Posted: 2024-03-29
• Primary Completion: 2026-10-31
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 628

Inclusion Criteria

• Adult patients hospitalized in an ICU
• Under mechanical ventilation for at least five days
• Microbiologically confirmed VAP preferably on a distal lung sample (bronchoalveolar lavage or protected distal specimen) otherwise endotracheal aspiration
• Enterobacteriaceae susceptible to cotrimoxazole, and for polymicrobial VAP, all bacteria susceptible to cotrimoxazole
• Treated for at least 24 hours by an appropriate empiric antibiotic therapy (at least one effective antibiotic from the initiation of treatment for this VAP episode)
• Stability of haemodynamic (stability or decrease in catecholamine dose) and respiratory (stability or improvement of FIO2) parameters

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Exclusion Criteria

• Haemodynamic instability (increasing dose of a catecholamine in the last 24 hours)

• Contra-indication to cotrimoxazole:

  • allergy,
  • advanced liver insufficiency,
  • renal dysfunction with clearance <15 mL/min/1.73 m² without hemodialysis
  • G6PD deficiency
  • history of hypersensitivity to one of the components (in particular, hypersensitivity to sulphonamides
  • known macrocytic anemia defined by VGM >
  • treatment with methotrexate

• Infection requiring prolonged antibiotic-therapy (pleural empyema, lung abscess, necrotizing pneumonia, etc...)

• Cystic fibrosis

• Immunosuppression (neutropenia, HIV with CD4 lymphocytes below 200/mm3, immunosuppressive therapy or corticosteroid therapy >0.5 mg/kg/j before ICU admission)

• Cardiac arrest without awakening

• Moribund state (patient likely to die within 24h)

• Limitation of life support (comfort care applied only) at the time of screening

• Enrolment to another interventional study on VAP care/management

• Pregnancy or breastfeeding

• Subject deprived of freedom, subject under a legal protective measure

• No affiliation to any health insurance system

• Refusal to participate to the study (patient or legal representative or family member or close relative if present)

• Patients previously included in the study

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
cotrimoxazole	cotrimoxazole	Use of cotrimoxazole for enterobacterial VAP. Posology and modalities of antibiotic administration will be optimized based on most recent recommendations for ICU patient. They will receive the treatment for 28 days or until death or until ICU discharge if its before 28days.
standard antibiotic therapy	standard antibiotic therapy	Use of standard antibiotic therapy enterobacterial VAP. Posology and modalities of antibiotic administration will be optimized based on most recent recommendations for ICU patient. They will receive the treatment for 28 days or until death or until ICU discharge if its before 28days.

Primary Outcome Measures

Name	Time	Method
To demonstrate that cotrimoxazole is non-inferior to best standard of care for the treatment of VAP in ICU in term of survival at day 28	28 days after inclusion	Vital status at day 28

Secondary Outcome Measures

Name	Time	Method
To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of VAP recurrence	28 days after inclusion	new episode of VAP with the same Enterobacteriaceae
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	28 days after inclusion	ICU length of stay
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	28 days after inclusion	Vital status at day 28
To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of overall antibiotic consumption	day 28 after inclusion	antibiotic-free days at day 28
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	90 days after inclusion	Vital status at day 90
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	28 days after inclusion	number of MV-free-days through day 28
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	days 7 and 10 after inclusion	Clinical, biological and radiological cure evaluated 7 to 10 days after VAP diagnosis, defined as the combination of resolution of signs and symptoms present at enrolment, biological improvement, and improvement or lack of progression of radiological signs, as adjudicated by an independent committee (PROBE methodology)
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	28 days after inclusion	hospital length of stay
To assess the safety of cotrimoxazole compared to best standard of care at day 28 in terms of allergy to antibiotics	28 days after inclusion	safety (rate of allergy due to antimicrobial drug)
To assess the ecological impact of the treatment in terms of acquisition of MDR bacteria in ICU	28 days after inclsuion	evolution of rate of MDR bacterial colonization on systematic screening at enrolment until ICU discharge
To assess the ecological impact of the treatment in terms of rate of Clostridioides difficile infection	28 days after inclusion	diagnostic of Clostridioides difficile infection between inclusion and day 28

Trial Locations

Locations (30)

Médecine Intensive Réanimation - Centre Hospitalier Universitaire Amiens-Picardie; 🇫🇷 Amiens, France

Médecine Intensive Réanimation - CHU Bordeaux - Hôpital Pellegrin; 🇫🇷 Bordeaux, France

Réanimation polyvalente et Unité de surveillance continue - Centre Hospitalier de Cholet; 🇫🇷 Cholet, France

Médecine Intensive Réanimation - Centre Hospitalier Départemental Vendée; 🇫🇷 La Roche-sur-Yon, France

Médecine Intensive Réanimation - Hôpital François Mitterrand; 🇫🇷 Dijon, France

Réanimation Médicale - Hôpital Robert Salengro; 🇫🇷 Lille, France

Réanimation médicale - Centre Hospitalier de Longjumeau; 🇫🇷 Longjumeau, France

Réanimation et Surveillance continue - Centre Hospitalier de Melun; 🇫🇷 Melun, France

Médecine Intensive Réanimation - Centre Hospitalier Léon Binet; 🇫🇷 Provins, France

Médecine Intensive Réanimation - CHRU de Nancy - Hôpitaux de Brabois; 🇫🇷 Nancy, France

Réanimation Médicale - Hôpital de la Pitié Salpêtrière; 🇫🇷 Paris, France

Médecine Intensive et Réanimation - Hôpital de la Pitié Salpêtrière; 🇫🇷 Paris, France

Médecine Intensive Réanimation - Hôpital René Dubos; 🇫🇷 Pontoise, France

Réanimation Polyvalente - Hôpital Sainte Musse; 🇫🇷 Toulon, France

Réanimation Polyvalente - Centre Hospitalier Annecy Genevois; 🇫🇷 Épagny, France

Médecine Intensive Réanimation - Centre Hospitalier Béthune - Beuvry; 🇫🇷 Béthune, France

Réanimation Médicale - Centre Jean Perrin - Site Gabriel Montpied; 🇫🇷 Clermont-Ferrand, France

Réanimation Médicale et Maladies Infectieuses - Hôpital Laennec; 🇫🇷 Nantes, France

Réanimation Médicale - Hôpital Européen Georges Pompidou; 🇫🇷 Paris, France

Médecine Intensive Réanimation - Hôpital Bretonneau; 🇫🇷 Tours, France

Centre Hospitalier Intercommunal Saint-Germain-en-Laye; 🇫🇷 Poissy, France

Médecine Intensive Réanimation - Nouvel Hôpital Civil; 🇫🇷 Strasbourg, France

Médecine Intensive Réanimation - Centre Hospitalier Universitaire Angers; 🇫🇷 Angers, France

Réanimation Médico-chirurgicale - Hôpital Ambroise-Paré; 🇫🇷 Boulogne-Billancourt, France

Médecin Intensive Réanimation - Hôpital Delafontaine; 🇫🇷 Saint-Denis, France

Médecine Intensive Réanimation - Hôpital Louis Mourier; 🇫🇷 Colombes, France

Réanimation polyvalente et surveillance continus - Centre Hospitalier Sud Francilien; 🇫🇷 Corbeil-Essonnes, France

Médecine Intensive Réanimation - Hôpital Michallon; 🇫🇷 La Tronche, France

Réanimation Médico-chirurgicale - Hôpital Avicenne; 🇫🇷 Bobigny, France

Réanimation Polyvalente - Centre Hospitalier Universitaire Nord Saint-Etienne; 🇫🇷 Saint-Priest-en-Jarez, France